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Although rapid progression and a poor prognosis in influenza A virus (IAV) infection–induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV‐induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV‐infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV‐inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1‐dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV‐infected pDHBE cells; however, these changes were rescued by OMA1‐siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV–induced cellular energy exhaustion via OMA1‐OPA1‐S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV. [ABSTRACT FROM AUTHOR]

In addition to controlling smooth muscle tone in coronary vessels, endothelial cells also influence subjacent cardiomyocyte growth. Because heparanase, with exclusive expression in endothelial cells, enables extracellular matrix remodeling, angiogenesis, metabolic reprogramming, and cell survival, it is conceivable that it could also encourage development of cardiac hypertrophy. Global heparanase overexpression resulted in physiologic cardiac hypertrophy, likely an outcome of HSPG clustering and activation of hypertrophic signaling. The heparanase autocrine effect of releasing neuregulin-1 could have also contributed to this overexpression. Hyperglycemia induced by streptozotocin-induced diabetes sensitized the heart to flow-induced release of heparanase and neuregulin-1. Despite this excess secretion, progression of diabetes caused significant gene expression changes related to mitochondrial metabolism and cell death that led to development of pathologic hypertrophy and heart dysfunction. Physiologic cardiac hypertrophy was also observed in rats with cardiomyocyte-specific vascular endothelial growth factor B overexpression. When perfused, hearts from these animals released significantly higher amounts of both heparanase and neuregulin-1. However, subjecting these animals to diabetes triggered robust transcriptome changes related to metabolism and a transition to pathologic hypertrophy. Our data suggest that in the absence of mechanisms that support cardiac energy generation and prevention of cell death, as seen after diabetes, there is a transition from physiologic to pathologic cardiac hypertrophy and a decline in cardiac function. Article Highlights: Endothelial cells have been implicated in physiologic cardiac hypertrophy. We examined the role of endothelial heparanase in this process and how diabetes affects heparanase function. Heparanase overexpression resulted in physiologic cardiac hypertrophy, an outcome of HSPG clustering and direct and indirect activation of hypertrophic signaling. Hyperglycemia sensitized the heart to flow-induced heparanase release, and progression of diabetes caused gene expression changes related to mitochondrial metabolism and apoptosis. With diabetes and its associated metabolic inflexibility and cell death, actions of heparanase are negated, leading to pathologic cardiac hypertrophy and heart dysfunction. These results can contribute to mechanism-directed therapeutics for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Organising pneumonia (OP) is one of the most common and lethal diseases in the category of interstitial pneumonia, along with lung cancer. Reprogramming of lipid metabolism is a newly recognized hallmark of many diseases including cancer, cardiovascular disorders, as well as liver fibrosis and sclerosis. Increased levels of ceramides composed of sphingosine and fatty acid, are implicated in the development of both acute and chronic lung diseases. However, their pathophysiological significance in OP is unclear. The aim of this study was to investigate the role of lipid metabolism reprogramming in OP, focusing on inflammation and fibrosis. Methods: Comprehensive multi‐omics profiling approaches, including single‐cell RNA sequencing, Visium CytAssist spatial transcriptomics, proteomics, metabolomics and mass spectrometry, were employed to analyze the tissues. OP mice model was utilized and molecular mechanisms were investigated in macrophages. Results: The results revealed a significant association between OP and lipid metabolism reprogramming, characterized by an abnormal expression of several genes related to lipid metabolism, including CD36, SCD1, and CES1 mainly in macrophages. CD36 deficiency in alveolar macrophages, led to an increased expression of C16/24 ceramides that accumulated in mitochondria, resulting in mitophagy or mitochondrial dysfunction. The number of alveolar macrophages in OP was significantly reduced, which was probably due to the ferroptosis signaling pathway involving GSH/SLC3A2/GPX4 through CD36 downregulation in OP. Furthermore, macrophage secretion of DPP7 and FABP4 influenced epithelial cell fibrosis. Conclusions: CD36 inhibited the ferroptosis pathway involving SLC3A2/GPX4 in alveolar macrophages of OP tissue by regulating lipid metabolism, thus representing a new anti‐ferroptosis and anti‐fibrosis effect of CD36 mediated, at least in part, by ceramides. Highlights: Our findings reveal a significant association between organising pneumonia and lipid metabolism reprogramming and will make a substantial contribution to the understanding of the mechanism of organising pneumonia in patients. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate‐limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)‐induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin‐10 (IL‐10). Methods: After nasal inhalation rIL‐10 and/or LPS, wild type (WT), IL‐10‐/‐, Cre‐CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow‐derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL‐10 and/or LPS. The qRT‐PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. Results: In in vivo experiments, we found that mice lacking CPT1A or IL‐10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL‐10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL‐10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL‐10‐/‐ BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL‐10 into macrophages showed reverse effect. CPT1A and IL‐10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A‐IL‐10 axis is also involved in the process of maintaining mitochondrial homeostasis. Conclusions: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL‐10/IL‐10 receptor expression. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia‐induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. Objective: To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia‐induced neuroinflammation and DNP and to explore potential therapeutic interventions. Method and Results: Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA‐sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia‐induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high‐glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy‐lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia‐induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia‐induced Sirt3 downregulation. Conclusion: Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP. [ABSTRACT FROM AUTHOR]

Cancer and senescent cells share many metabolic features that contribute to their common and unique cellular states. Senescent cells alter both glucose and non-glucose metabolism, including glycolysis, mitochondrial respiration, fatty acid oxidation, and glutaminolysis, to meet their bioenergetic, biosynthetic, and redox homeostatic needs. Senescent cells sustain metabolic signaling pathways in a hardwired manner to direct their metabolic alterations toward pathological anabolic processes. Senescent cells may rely on protein degradation pathways to mitigate errors caused by their hyperactivated anabolism, such as the senescence-associated secretory phenotype (SASP). Targeting senescence metabolism, analogous to targeting cancer metabolism, sensitizes senescent cells or suppresses the SASP, thereby serving as a new therapeutic modality for senotherapy. Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells – a critical component of the aging process – undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients. Metabolic reprogramming is crucial in tumorigenesis, with alterations in glucose and fatty acid metabolism playing key roles. Here, the authors show that inhibiting fatty acid oxidation in HER2-driven breast cancers delays tumor growth and enhances the effectiveness of HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity. Editor's summary: After initial antigen encounter, some T cells persist and differentiate into long-lived memory cells. This process is accompanied by metabolic reprogramming that supports survival and memory functions, but the key factors driving memory T cell metabolic adaptation remain unclear. Using mouse models of viral infection and melanoma, Bevilacqua et al. found that the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) supports the switch from aerobic glycolysis to oxidative metabolism during central memory CD8+ T cell formation. PPARβ/δ expression was required for memory T cell responses upon rechallenge, as well as the generation of TCF-1+ progenitor exhausted T cells during chronic antigen exposure. Together, these findings identify PPARβ/δ as a key regulator of metabolic reprogramming during memory T cell differentiation. —Claire Olingy [ABSTRACT FROM AUTHOR]

MARCH5 is a ring-finger E3 ubiquitin ligase located in the outer membrane of mitochondria. A previous study has reported that MARCH5 was up-regulated and contributed to the migration and invasion of OC cells by serving as a competing endogenous RNA. However, as a mitochondrial localized E3 ubiquitin ligase, the function of MARCH5 in mitochondrial-associated metabolism reprogramming in human cancers remains largely unexplored, including OC. We first assessed the glycolysis effect of MARCH5 in OC both in vitro and in vivo. Then we analyzed the effect of MARCH5 knockdown or overexpression on respiratory activity by evaluating oxygen consumption rate, activities of OXPHOS complexes and production of ATP in OC cells with MARCH5. Co-immunoprecipitation, western-blot, and in vitro and vivo experiments were performed to investigate the molecular mechanisms underlying MARCH5-enhanced aerobic glycolysis s in OC. In this study, we demonstrate that the abnormal upregulation of MARCH5 is accompanied by significantly increased aerobic glycolysis in OC. Mechanistically, MARCH5 promotes aerobic glycolysis via ubiquitinating and degrading mitochondrial pyruvate carrier 1 (MPC1), which mediates the transport of cytosolic pyruvate into mitochondria by localizing on mitochondria outer membrane. In line with this, MPC1 expression is significantly decreased and its downregulation is closely correlated with unfavorable survival. Furthermore, in vitro and in vivo assays revealed that MARCH5 upregulation-enhanced aerobic glycolysis played a critical role in the proliferation and metastasis of OC cells. Taken together, we identify a MARCH5-regulated aerobic glycolysis mechanism by degradation of MPC1, and provide a rationale for therapeutic targeting of aerobic glycolysis via MARCH5-MPC1 axis inhibition. [ABSTRACT FROM AUTHOR]

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll‐like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy. [ABSTRACT FROM AUTHOR]

The efficacy of transarterial chemoembolization (TACE) has been limited by insufficient embolization and a high incidence of tumor recurrence. Herein, we identified that aberrant metabolic reprogramming and immunosuppression contribute to TACE refractoriness and Rhein, as a potential glycolytic metabolism inhibitor and immunoactivation inducer, was optimized to sensitize tumors to TACE therapy. To achieve efficient embolization, we developed an oil‐in‐water lipiodol embolic emulsion by stabilizing the self‐assembled Rhein nanogel. The assembled Rhein exhibited a nanofiber network, and its integration enhanced the mechanical stability and viscoelasticity of the lipiodol embolic agent. With the synergistic advantages of solid and liquid embolic agents, this carrier‐free Pickering emulsion exhibits efficient embolization and sustained drug release in models of unilateral renal artery embolization, rabbit ear tumor embolization, rabbit orthotopic liver cancer, and rat orthotopic liver cancer. Compared to conventional three‐way catheter mixing methods, multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression. Importantly, the incorporation of Rhein‐mediated synergistic immunoembolization in this strategy achieved efficient embolization while robustly activating anti‐tumor immune responses, including inducing immunogenic cell death, dendritic cell activation, and major histocompatibility complex class I presentation to CD8+ T cells for tumor killing. Together, these findings reveal a novel strategy for the application of self‐assembled Rhein nanofiber‐stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal‐like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal‐like/squamous subtype. Using our integrated approach, we identified endosome–lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI‐UMD‐German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal‐like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1‐Methylnicotinamide, a known oncometabolite derived from S‐adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal‐like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC. [ABSTRACT FROM AUTHOR]

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17β‐estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2‐silenced E2‐treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC. Highlights: Colorectal cancer (CRC) cells exhibit a versatile metabolic profile that is responsive to changes in the tumor microenvironment.Estrogen (E2) signaling modulates glycolysis and reduces CRC cell growth and survival.Pyruvate kinase M2 (PKM2) inhibition also modulates glycolysis and reduces CRC cell growth.Combining E2 treatment with PKM2 inhibition precipitates significant cumulative antitumor effects in CRC cells. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a key pathological basis for cardiovascular diseases, significantly influenced by T-cell-mediated immune responses. T-cells differentiate into various subtypes, such as pro-inflammatory Th1/Th17 and anti-inflammatory Th2/Treg cells. The imbalance between these subtypes is critical for the progression of atherosclerosis (AS). Recent studies indicate that metabolic reprogramming within various microenvironments can shift T-cell differentiation towards pro-inflammatory or anti-inflammatory phenotypes, thus influencing AS progression. This review examines the roles of pro-inflammatory and anti-inflammatory T-cells in atherosclerosis, focusing on how their metabolic reprogramming regulates AS progression and the associated molecular mechanisms of mTOR and AMPK signaling pathways. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential. [ABSTRACT FROM AUTHOR]

Although growing evidence suggests close correlations between Alzheimer's disease (AD) and circadian rhythm disruption (CRD), few studies have focused on the influence of circadian rhythm on levels of immune cells in AD. We aimed to delineate the mechanism underlying the effects of circadian related genes on T cell immune function in AD. A total of 112 brain samples were used to construct the CRD-related model by performing weighted gene co-expression network analysis and machine learning algorithms (LASSO, SVM-RFE, and RF). The ssGSEA method was used to calculate the CRDscore in order to quantify CRD status. Using single-cell transcriptome data of CSF cells, we investigated the CD4+ T cell metabolism and cell-cell communication in high- and low-risk CRD groups. Connectivity map (CMap) was applied to explore small molecule drugs targeting CRD, and the expression of the signature gene GPR4 was further validated in AD. The CRDscore algorithm, which is based on 23 circadian-related genes, can effectively classify the CRD status in AD datasets. The single-cell analysis revealed that the CD4+ T cells with high CRDscore were characterized by hypometabolism. Cell communication analysis revealed that CD4+ T cells might be involved in promoting CD8+ T cell adhesion under CRD, which may facilitate T cell infiltration into the brain parenchyma. Overall, this study indicates the potential connotation of circadian rhythm in AD, providing insights into understanding T cell metabolic reprogramming under CRD. [ABSTRACT FROM AUTHOR]

The aetiology of bone metastasis in prostate cancer (PCa) remains unclear. This study aims to identify hub genes involved in this process. We utilized machine learning, GO, KEGG, GSEA, Single‐cell analysis, ROC methods to identify hub genes for bone metastasis in PCa using the TCGA and GEO databases. Potential drugs targeting these genes were identified. We validated these results using 16 specimens from patients with PCa and analysed the relationship between the hub genes and clinical features. The impact of APOC1 on PCa was assessed through in vitro experiments. Seven hub genes with AUC values of 0.727–0.926 were identified. APOC1, CFH, NUSAP1 and LGALS1 were highly expressed in bone metastasis tissues, while NR4A2, ADRB2 and ZNF331 exhibited an opposite trend. Immunohistochemistry further confirmed these results. The oxidative phosphorylation pathway was significantly enriched by the identified genes. Aflatoxin B1, benzo(a)pyrene, cyclosporine were identified as potential drugs. APOC1 expression was correlated with clinical features of PCa metastasis. Silencing APOC1 significantly inhibited PCa cell proliferation, clonality, and migration in vitro. This study identified 7 hub genes that potentially facilitate bone metastasis in PCa through mitochondrial metabolic reprogramming. APOC1 emerged as a promising therapeutic target and prognostic marker for PCa with bone metastasis. [ABSTRACT FROM AUTHOR]

Application of physical forces, ranging from ultrasound to electric fields, is recommended in various clinical practice guidelines, including those for treating cancers and bone fractures. However, the mechanistic details of such treatments are often inadequately understood, primarily due to the absence of comprehensive study models. In this study, we demonstrate that an alternating magnetic field (AMF) inherently possesses a direct anti‐cancer effect by enhancing oxidative phosphorylation (OXPHOS) and thereby inducing metabolic reprogramming. We observed that the proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz. In contrast, this exposure did not affect normal human astrocytes (NHA). Additionally, in mouse models implanted with human GBM cells in the brain, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival. This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression. The anti‐cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger. Along with these observations, there was a decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR). This suggests that AMF‐induced metabolic reprogramming occurs in GBM cells but not in normal cells. Our results suggest that AMF exposure may offer a straightforward strategy to inhibit cancer cell growth by leveraging oxidative stress through metabolic reprogramming. [ABSTRACT FROM AUTHOR]

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches. [ABSTRACT FROM AUTHOR]

Background: It has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure. Method: Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC–MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter. Results: Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells. Conclusion: We reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies. [ABSTRACT FROM AUTHOR]

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression. [ABSTRACT FROM AUTHOR]

SARIFA was very recently introduced as a histomorphological biomarker with strong prognostic power for colorectal, gastric, prostate, and pancreatic cancer. It is characterized by the direct contact between tumor cells and adipocytes due to a lack of stromal reaction. This can be easily evaluated on routinely available H&E-slides with high interobserver agreement. SARIFA also reflects a specific tumor biology driven by metabolic reprogramming. Tumor cells in SARIFA-positive tumors benefit from direct interaction with adipocytes as an external source of lipids. Numerous studies have shown that lipid metabolism is crucial in carcinogenesis and cancer progression. We found that the interaction between tumor cells and adipocytes was not triggered by obesity, as previously assumed. Instead, we believe that this is due to an immunological mechanism. Knowledge about lipid metabolism in cancer from basic experiments can be transferred to develop strategies targeting this reprogramed metabolism. [ABSTRACT FROM AUTHOR]

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis. Pro-inflammatory signals trigger innate immune pathways with consequential metabolic remodeling. Here authors show that a rate-limiting enzymes of glycolysis, PFKL, is directly regulated by innate stimuli via phosphorylation at Ser775, which modification in turn influences pro-inflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Background and aims: Metabolic reprogramming has been found to be a typical feature of tumors. Hepatocellular carcinoma (HCC), a cancer with high morbidity and mortality, has been extensively studied for its metabolic reprogrammingrelated mechanisms. Our study aims to identify the hotspots and frontiers of metabolic reprogramming research in HCC and to provide guidance for future scientific research and decision-making in HCC metabolism. Methods: Relevant studies on the metabolic reprogramming of HCC were derived from the Web of Science Core Collection (WoSCC) database up until November 2023. The bibliometrix tools in R were used for scientometric analysis and visualization. Results: From 2011 to 2023, a total of 575 publications were obtained from WoSCC that met the established criteria. These publications involved 3,904 researchers and 948 organizations in 37 countries, with an average annual growth rate of 39.11% in research. These studies were published in 233 journals, with Cancers (n = 29) ranking first, followed by Frontiers in Oncology (n = 20) and International Journal of Molecular Sciences (n = 19). The top ten journals accounted for 26% of the 575 studies. The most prolific authors were Wang J (n = 14), Li Y (n = 12), and Liu J (n = 12). The country with the most publications is China, followed by the United States, Italy, and France. Fudan University had the largest percentage of research results with 15.48% (n = 89). Ally A's paper in Cell has the most citations. A total of 1,204 keywords were analyzed, with the trend themes such as "glycolysis," "tumor microenvironment," "Warburg effect," "mitochondria," "hypoxia," etc. Co-occurrence network and cluster analysis revealed the relationships between keywords, authors, publications, and journals. Moreover, the close collaboration between countries in this field was elucidated. Conclusion: This bibliometric and visual analysis delves into studies related to metabolic reprogramming in HCC between 2012 and 2023, elucidating the characteristics of research in this field, which has gradually moved away from single glycolipid metabolism studies to the integration of overall metabolism in the body, pointing out the trend of research topics, and the dynamics of the interaction between the tumor microenvironment and metabolic reprogramming will be the future direction of research, which provides blueprints and inspirations for HCC prevention and treatment programs to the researchers in this field. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and are related to tumor proliferation, metastasis, relapse, and drug resistance. With the development of sequencing technologies, single-cell RNA sequencing has become a popular method for identifying CAFs in the tumor microenvironment. Whereas the drawbacks of CAFs, such as the lack of a spatial landscape, still exist, recent research has utilized spatial transcriptomics combined with single-cell RNA sequencing to address this issue. These multiomics analyses can resolve the single-cell resolution problem in spatial transcriptomics. In this review, we summarized the recent literature regarding the targeting of CAFs to address drug resistance, angiogenesis, metabolic reprogramming and metastasis in tumor tissue. [ABSTRACT FROM AUTHOR]

Type-2 diabetes (T2D) is a rapidly growing multifactorial metabolic disorder that induces the onset of various diseases in the human body. The compositional and metabolic shift of the gut microbiota is a crucial factor behind T2D. Hence, gaining insight into the metabolic profile of the gut microbiota is essential for revealing their role in regulating the metabolism of T2D patients. Here, we have focused on the genome-scale community metabolic model reconstruction of crucial T2D-associated gut microbes. The model-based analysis of biochemical flux in T2D and healthy gut conditions showed distinct biochemical signatures and diverse metabolic interactions in the microbial community. The metabolic interactions encompass cross-feeding of short-chain fatty acids, amino acids, and vitamins among individual microbes within the community. In T2D conditions, a reduction in the metabolic flux of acetate, butyrate, vitamin B5, and bicarbonate was observed in the microbial community model, which can impact carbohydrate metabolism. The decline in butyrate levels is correlated with both insulin resistance and diminished glucose metabolism in T2D patients. Compared to the healthy gut, an overall reduction in glucose consumption and SCFA production flux was estimated in the T2D gut environment. Moreover, the decreased consumption profiles of branch chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the T2D gut microbiota can be a distinct biomarker for T2D. Hence, the flux-level analysis of the microbial community model can provide insights into the metabolic reprogramming in diabetic gut microbiomes, which may be helpful in personalized therapeutics and diet design against T2D. [ABSTRACT FROM AUTHOR]

Lipid metabolism reprogramming involves in epithelial-mesenchymal transition (EMT), cancer stemness and immune checkpoints (ICs), which influence the metastasis of cancer. This study aimed to generate lipid metabolism-based signatures to predict prognosis, immunotherapy and chemotherapy response for colorectal adenocarcinoma (COAD). Transcriptome data and clinical information of COAD patients were collected from the cancer genome atlas (TCGA) database. The expression of EMT-, stem cell-, and IC-related genes were assessed between COAD and control samples. Modules and genes correlated EMT, ICs and stemness signatures were identified through weighted gene co-expression network analysis (WGCNA). Prognostic signatures were generated and then the distribution of risk genes was evaluated using single-cell RNA sequencing (scRNA-seq) data from GSE132465 dataset. COAD patients exhibited increased EMT score and stemness along with decreased ICs. Next, 12 hub genes (PIK3CG, ALOX5AP, PIK3R5, TNFAIP8L2, DPEP2, PIK3CD, PIK3R6, GGT5, ELOVL4, PTGIS, CYP7B1 and PRKD1) were found within green and yellow modules correlated with EMT, stemness and ICs. Lipid metabolism-based prognostic signatures were generated based on PIK3CG, GGT5 and PTGIS. Patients with high-risk group had poor prognosis, elevated ESTIMATEScore and StromalScore, 100% mutation rate and higher TIDE score. Samples in low-risk group had more immunogenicity on ICIs. Notably, PIK3CG was expressed in B cells, while GGT5 and PTGIS were expressed in stromal cells. This study generates lipid metabolism-based signatures correlated with EMT, stemness and ICs for predicting prognosis of COAD, and provides potential therapeutic targets for immunotherapy in COAD. [ABSTRACT FROM AUTHOR]

Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin–proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues. [ABSTRACT FROM AUTHOR]

Background: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. Methods: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. Results: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. Conclusions: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine. [ABSTRACT FROM AUTHOR]

The RNA modification, 5‐methylcytosine (m5C), has recently gained prominence as a pivotal post‐transcriptional regulator of gene expression, intricately intertwined with various tumorigenic processes. However, the exact mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain unclear. Here, it is determined that the m5C methyltransferase NSUN2 exhibits significantly elevated expression and exerts an oncogenic function in CRC. Mechanistically, NSUN2 and YBX1 are identified as the "writer" and "reader" of ENO1, culminating in the reprogramming of the glucose metabolism and increased production of lactic acid in an m5C‐dependent manner. The accumulation of lactic acid derived from CRC cells, in turn, activates the transcription of NSUN2 through histone H3K18 lactylation (H3K18la), and induces the lactylation of NSUN2 at the Lys356 residue (K356), which is crucial for capturing target RNAs. Together, these findings reveal an intriguing positive feedback loop involving the NSUN2/YBX1/m5C‐ENO1 signaling axis, thereby bridging the connection between metabolic reprogramming and epigenetic remodeling, which may shed light on the therapeutic potential of combining an NSUN2 inhibitor with immunotherapy for CRC. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood. Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors. Results and discussion: Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPSinduced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, overproliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis. [ABSTRACT FROM AUTHOR]

Mycobacteria adapt to infection stresses by entering a reversible non-replicating persistence (NRP) with slow or no cell growth and broad antimicrobial tolerance. Hypoxia and nutrient deprivation are two well-studied stresses commonly used to model the NRP, yet little is known about the molecular differences in mycobacterial adaptation to these distinct stresses that lead to a comparable NRP phenotype. Here we performed a multisystem interrogation of the Mycobacterium bovis BCG (BCG) starvation response, which revealed a coordinated metabolic shift away from the glycolysis of nutrient-replete growth to depletion of lipid stores, lipolysis, and fatty acid ß-oxidation in NRP. This contrasts with BCG's NRP hypoxia response involving a shift to cholesterol metabolism and triglyceride storage. Our analysis reveals cryptic metabolic vulnerabilities of the starvation-induced NRP state, such as their newfound hypersensitivity to H2O2. These observations pave the way for developing precision therapeutics against these otherwise drug refractory pathogens. A multi-omics comparison of the mycobacterial response to hypoxia and starvation reveals that distinct differences in fatty acid and cholesterol metabolism lead to the same non-replicating, drug-tolerant persistence phenotype. [ABSTRACT FROM AUTHOR]

Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as ß-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation--a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training. [ABSTRACT FROM AUTHOR]

Highlights: A large-scale metabolic adaptation in M1-polarized macrophages compared with M2 macrophages, along with multiple altered metabolite parameters that can serve as potential targets, have been discussed. Nanomaterial-based repurposing of macrophage metabolism and its applications are systematically summarized and illustrated using representative examples. Potential challenges, additional information about future research objectives, and priorities of nanomaterial-based macrophage immunotherapy are highlighted. Macrophage immunotherapy represents an emerging therapeutic approach aimed at modulating the immune response to alleviate disease symptoms. Nanomaterials (NMs) have been engineered to monitor macrophage metabolism, enabling the evaluation of disease progression and the replication of intricate physiological signal patterns. They achieve this either directly or by delivering regulatory signals, thereby mapping phenotype to effector functions through metabolic repurposing to customize macrophage fate for therapy. However, a comprehensive summary regarding NM-mediated macrophage visualization and coordinated metabolic rewiring to maintain phenotypic equilibrium is currently lacking. This review aims to address this gap by outlining recent advancements in NM-based metabolic immunotherapy. We initially explore the relationship between metabolism, polarization, and disease, before delving into recent NM innovations that visualize macrophage activity to elucidate disease onset and fine-tune its fate through metabolic remodeling for macrophage-centered immunotherapy. Finally, we discuss the prospects and challenges of NM-mediated metabolic immunotherapy, aiming to accelerate clinical translation. We anticipate that this review will serve as a valuable reference for researchers seeking to leverage novel metabolic intervention-matched immunomodulators in macrophages or other fields of immune engineering. [ABSTRACT FROM AUTHOR]

Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer (PCa), is characterized by loss of AR signaling and resistance to AR-targeted therapy. While it is well reported that second-generation AR blockers induce neuroendocrine (NE) trans-differentiation of castration-resistant prostate cancer (CRPC) to promote the occurrence of NEPC, and pluripotent transcription factors might be potential regulators, the underlying molecular mechanisms remain unclear. Methods: We analyzed the data from public databsets to screen candidate genes and then focused on SOX4, a regulator of NE trans-differentiation. The expression changes of SOX4 and its relationship with tumor progression were validated in clinical tumor tissues. We evaluated malignant characteristics related to NEPC in prostate cancer cell lines with stable overexpression or knockdown of SOX4 in vitro. Tumor xenografts were analyzed after inoculating the relevant cell lines into nude mice. RNA-seq, ATAC-seq, non-targeted metabolomics analysis, as well as molecular and biochemical assays were carried out to determine the mechanism. Results: We screened public datasets and identified that expression of SOX4 was significantly elevated in NEPC. Overexpressing SOX4 in C4-2B cells increased cell proliferation and migration, upregulated the expression of NE marker genes, and inhibited AR expression. Consistently, inhibition of SOX4 expression in DU-145 and PC-3 cells reduced the above malignant phenotypes and repressed the expression of NE marker genes. For the in vivo assay, we found that knockdown of SOX4 inhibited tumor growth of subcutaneous xenografts in castrated nude mice which were concomitantly treated with enzalutamide (ENZ). Mechanically, we identified that one of the key enzymes in gluconeogenesis, PCK2, was a novel target of SOX4. The activation of carbohydrate metabolism reprogramming by SOX4 could promote NE trans-differentiation via the SOX4/PCK2 pathway. Conclusions: Our findings reveal that SOX4 promotes NE trans-differentiation both in vitro and in vivo via directly enhancing PCK2 activity to activate carbohydrate metabolism reprogramming. The SOX4/PCK2 pathway and its downstream changes might be novel targets for blocking NE trans-differentiation. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is an increasing cause of cancer-related death, with a dismal prognosis caused by its aggressive biology, the lack of clinical symptoms in the early phases of the disease, and the inefficacy of treatments. PC is characterized by a complex tumor microenvironment. The interaction of its cellular components plays a crucial role in tumor development and progression, contributing to the alteration of metabolism and cellular hyperproliferation, as well as to metastatic evolution and abnormal tumor-associated immunity. Furthermore, in response to intrinsic oncogenic alterations and the influence of the tumor microenvironment, cancer cells undergo a complex oncogene-directed metabolic reprogramming that includes changes in glucose utilization, lipid and amino acid metabolism, redox balance, and activation of recycling and scavenging pathways. The advent of omics sciences is revolutionizing the comprehension of the pathogenetic conundrum of pancreatic carcinogenesis. In particular, metabolomics and genomics has led to a more precise classification of PC into subtypes that show different biological behaviors and responses to treatments. The identification of molecular targets through the pharmacogenomic approach may help to personalize treatments. Novel specific biomarkers have been discovered using proteomics and metabolomics analyses. Radiomics allows for an earlier diagnosis through the computational analysis of imaging. However, the complexity, high expertise required, and costs of the omics approach are the main limitations for its use in clinical practice at present. In addition, the studies of extracellular vesicles (EVs), the use of organoids, the understanding of host–microbiota interactions, and more recently the advent of artificial intelligence are helping to make further steps towards precision and personalized medicine. This present review summarizes the main evidence for the application of omics sciences to the study of PC and the identification of future perspectives. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and is a major cause of cancer-related mortality in the world. This study aimed to characterize glutamine amino acid transporter expression profiles in HCC compared to those of normal liver cells. In vitro and in vivo models of HCC were studied using qPCR, whereas the prognostic significance of glutamine transporter expression levels within patient tumors was analyzed through RNAseq. Solute carrier (SLC) 1A5 and SLC38A2 were targeted through siRNA or gamma-p-nitroanilide (GPNA). HCC cells depended on exogenous glutamine for optimal survival and growth. Murine HCC cells showed superior glutamine uptake rate than normal hepatocytes (p < 0.0001). HCC manifested a global reprogramming of glutamine transporters compared to normal liver: SLC38A3 levels decreased, whereas SLC38A1, SLC7A6, and SLC1A5 levels increased. Also, decreased SLC6A14 and SLC38A3 levels or increased SLC38A1, SLC7A6, and SLC1A5 levels predicted worse survival outcomes (all p < 0.05). Knockdown of SLC1A5 and/or SLC38A2 expression in human Huh7 and Hep3B HCC cells, as well as GPNA-mediated inhibition, significantly decreased the uptake of glutamine; combined SLC1A5 and SLC38A2 targeting had the most considerable impact (all p < 0.05). This study revealed glutamine transporter reprogramming as a novel hallmark of HCC and that such expression profiles are clinically significant. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignant tumor worldwide. Despite enormous progress made in the past decades, the underlying mechanisms of BC remain further illustrated. Recently, TRIM family proteins proved to be engaged in BC progression through regulating various aspects. Here we reviewed the structures and basic functions of TRIM family members and first classified them into three groups according to canonical polyubiquitination forms that they could mediate: K48‐ only, K63‐ only, and both K48‐ and K63‐linked ubiquitination. Afterwards, we focused on the specific biological functions and mechanisms of TRIMs in BCs, including tumorigenesis and invasiveness, drug sensitivity, tumor immune microenvironment (TIME), cell cycle, and metabolic reprogramming. We also explored the potential of TRIMs as novel biomarkers for predicting prognosis and future therapeutic targets in BC. [ABSTRACT FROM AUTHOR]

Mitophagy is the cellular process to selectively eliminate dysfunctional mitochondria, governing the number and quality of mitochondria. Dysregulation of mitophagy may lead to the accumulation of damaged mitochondria, which plays an important role in the initiation and development of tumors. Mitophagy includes ubiquitin-dependent pathways mediated by PINK1/Parkin and non-ubiquitin dependent pathways mediated by mitochondrial autophagic receptors including NIX, BNIP3, and FUNDC1. Cellular mitophagy widely participates in multiple cellular process including metabolic reprogramming, anti-tumor immunity, ferroptosis, as well as the interaction between tumor cells and tumor-microenvironment. And cellular mitophagy also regulates tumor proliferation and metastasis, stemness, chemoresistance, resistance to targeted therapy and radiotherapy. In this review, we summarized the underlying molecular mechanisms of mitophagy and discussed the complex role of mitophagy in diverse contexts of tumors, indicating it as a promising target in the mitophagy-related anti-tumor therapy. [ABSTRACT FROM AUTHOR]

Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer. [ABSTRACT FROM AUTHOR]

Fusarium oxysporum f. sp. lentis (Fol) is considered the most destructive disease for lentil (Lens culinaris Medik.) worldwide. Despite the extensive studies elucidating plants' metabolic response to fungal agents, there is a knowledge gap in the biochemical mechanisms governing Fol-resistance in lentil. Τhis study aimed at comparatively evaluating the metabolic response of two lentil genotypes, with contrasting phenotypes for Fol-resistance, to Fol-inoculation. Apart from gaining insights into the metabolic reprogramming in response to Fol-inoculation, the study focused on discovering novel biomarkers to improve early selection for Fol-resistance. GC-MS-mediated metabolic profiling of leaves and roots was employed to monitor changes across genotypes and treatments as well as their interaction. In total, the analysis yielded 178 quantifiable compounds, of which the vast majority belonged to the groups of carbohydrates, amino acids, polyols and organic acids. Despite the magnitude of metabolic fluctuations in response to Fol-inoculation in both genotypes under study, significant alterations were noted in the content of 18 compounds, of which 10 and 8 compounds referred to roots and shoots, respectively. Overall data underline the crucial contribution of palatinitol and L-proline in the metabolic response of roots and shoots, respectively, thus offering possibilities for their exploitation as metabolic biomarkers for Fol-resistance in lentil. To the best of our knowledge, this is the first metabolomics-based approach to unraveling the effects of Fol-inoculation on lentil's metabolome, thus providing crucial information related to key aspects of lentil–Fol interaction. Future investigations in metabolic aspects of lentil–Fol interactions will undoubtedly revolutionize the search for metabolites underlying Fol-resistance, thus paving the way towards upgrading breeding efforts to combat fusarium wilt in lentil. [ABSTRACT FROM AUTHOR]

Liver cancer is a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form, characterized by high incidence and mortality rates. Despite advances in targeted therapies and immunotherapies, the prognosis for advanced liver cancer remains poor. This underscores the urgent need for a deeper understanding of the molecular mechanisms underlying HCC to enable early detection and the development of novel therapeutic strategies. Post-translational modifications (PTMs) are crucial regulatory mechanisms in cellular biology, affecting protein functionality, interactions, and localization. These modifications, including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation, occur after protein synthesis and play vital roles in various cellular processes. Recent advances in proteomics and molecular biology have highlighted the complex networks of PTMs, emphasizing their critical role in maintaining cellular homeostasis and disease pathogenesis. Dysregulation of PTMs has been associated with several malignant cellular processes in HCC, such as altered cell proliferation, migration, immune evasion, and metabolic reprogramming, contributing to tumor growth and metastasis. This review aims to provide a comprehensive understanding of the pathological mechanisms and clinical implications of various PTMs in liver cancer. By exploring the multifaceted interactions of PTMs and their impact on liver cancer progression, we highlight the potential of PTMs as biomarkers and therapeutic targets. The significance of this review lies in its potential to inform the development of novel therapeutic approaches and improve prognostic tools for early intervention in the fight against liver cancer. [ABSTRACT FROM AUTHOR]

Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients. [ABSTRACT FROM AUTHOR]

Background: Clear Cell Renal Cell Carcinoma (ccRCC) is the most common type of kidney cancer, characterized by high heterogeneity and complexity. Recent studies have identified mitochondrial defects and autophagy as key players in the development of ccRCC. This study aims to delve into the changes in mitophagic activity within ccRCC and its impact on the tumor microenvironment, revealing its role in tumor cell metabolism, development, and survival strategies. Methods: Comprehensive analysis of ccRCC tumor tissues using single cell sequencing and spatial transcriptomics to reveal the role of mitophagy in ccRCC. Mitophagy was determined to be altered among renal clear cells by gene set scoring. Key mitophagy cell populations and key prognostic genes were identified using NMF analysis and survival analysis approaches. The role of UBB in ccRCC was also demonstrated by in vitro experiments. Results: Compared to normal kidney tissue, various cell types within ccRCC tumor tissues exhibited significantly increased levels of mitophagy, especially renal clear cells. Key genes associated with increased mitophagy levels, such as UBC, UBA52, TOMM7, UBB, MAP1LC3B, and CSNK2B, were identified, with their high expression closely linked to poor patient prognosis. Particularly, the ubiquitination process involving the UBB gene was found to be crucial for mitophagy and its quality control. Conclusion: This study highlights the central role of mitophagy and its regulatory factors in the development of ccRCC, revealing the significance of the UBB gene and its associated ubiquitination process in disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic reprogramming is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC). A pancreatic juice (PJ) metabolic signature has been reported to be prognostic of oncological outcome for PDAC. Integration of PJ profiling with transcriptomic and spatial characterization of the tumor microenvironment would help in identifying PDACs with peculiar vulnerabilities. Methods: We performed a transcriptomic analysis of 26 PDAC samples grouped into 3 metabolic clusters (M_CL) according to their PJ metabolic profile. We analyzed molecular subtypes and transcriptional differences. Validation was performed by multidimensional imaging on tumor slides. Results: Pancreatic juice metabolic profiling was associated with PDAC transcriptomic molecular subtypes (p=0.004). Tumors identified as M_CL1 exhibited a non-squamous molecular phenotype and demonstrated longer survival. Enrichment analysis revealed the upregulation of immune genes and pathways in M_CL1 samples compared to M_CL2, the group with worse prognosis, a difference confirmed by immunofluorescence on tissue slides. Enrichment analysis of 39 immune signatures by xCell confirmed decreased immune signatures in M_CL2 compared to M_CL1 and allowed a stratification of patients associated with longer survival. Discussion: PJ metabolic fingerprints reflect PDAC molecular subtypes and the immune microenvironment, confirming PJ as a promising source of biomarkers for personalized therapy. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in China. Due to the lack of effective molecular targets, the prognosis of ESCC patients is poor. It is urgent to explore the pathogenesis of ESCC to identify promising therapeutic targets. Metabolic reprogramming is an emerging hallmark of ESCC, providing a novel perspective for revealing the biological features of ESCC. In the hypoxic and nutrient-limited tumor microenvironment, ESCC cells have to reprogram their metabolic phenotypes to fulfill the demands of bioenergetics, biosynthesis and redox homostasis of ESCC cells. In this review, we summarized the metabolic reprogramming of ESCC cells that involves glucose metabolism, lipid metabolism, and amino acid metabolism and explore how reprogrammed metabolism provokes novel opportunities for biomarkers and potential therapeutic targets of ESCC. [ABSTRACT FROM AUTHOR]

The most prevalent primary brain tumors in adults are gliomas. In addition to insufficient therapeutic alternatives, gliomas are fatal mostly due to the rapid proliferation and continuous infiltration of tumor cells into the surrounding healthy brain tissue. According to a growing body of research, aerobic glycolysis, or the Warburg effect, promotes glioma development because gliomas are heterogeneous cancers that undergo metabolic reprogramming. Therefore, addressing the Warburg effect might be a useful therapeutic strategy for treating cancer. Lactate plays a critical role in reprogramming energy metabolism, allowing cells to rapidly access large amounts of energy. Lactate, a byproduct of glycolysis, is therefore present in rapidly proliferating cells and tumors. In addition to the protumorigenesis pathways of lactate synthesis, circulation, and consumption, lactate-induced lactylation has been identified in recent investigations. Lactate plays crucial roles in modulating immune processes, maintaining homeostasis, and promoting metabolic reprogramming in tumors, which are processes regulated by the lactate-induced lactylation of the lysine residues of histones. In this paper, we discuss the discovery and effects of lactylation, review the published studies on how protein lactylation influences cancer growth and further explore novel treatment approaches to achieve improved antitumor effects by targeting lactylation. These findings could lead to a new approach and guidance for improving the prognosis of patients with gliomas. [ABSTRACT FROM AUTHOR]