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In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.

This research is the first study of McIntosh apple cider fermentation using different must treatments. The must materials included standard pressed juice, the common cider fermentation material, mash, direct from the apple shredder both with and without pectinase additions, and finally, pomace. These four treatments caused multiple differences from the standard hard ciders from juice, starting with the apple must characteristics, following through the yeast fermentation processes, and carried into the final ciders. Initial apple musts had different sugar content, pH, acids, total phenolics, and antioxidant activities. Although juice contained more total phenolics and had more antioxidant capabilities, it contained lower levels of yeast assimilable nitrogen. The sugar consumption dynamic changes had a differential dynamic trend but did not alter the capacity for complete apple cider fermentation. From the fermentation color dynamic changes, it indicated that must materials would have effects on color-changing amplitudes. Juice treatment had the largest changes from the must. Pomace and mash with pectinase had fewer color changes in multiple color values (L*, a*, b*). The mono phenolics in the final cider indicated that pomace ferments contained the least hydroxycinnamates but a similar amount of total flavanols as juice-fermented ciders. Cider from the juice contained the least flavonols, whereas the mash, both with and without pectinase treatments, had the largest amount of flavonols. This work will provide some applicable information for apple cider fermentation from the apple wastes in the cider industry.

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.

The desire of every broiler farmer is to produce birds with fast growth rate and good weight for both marketing and consumption. This objective can only be achieved under a good feeding regime. The physical form of the feed offered is therefore a critical factor in achieving this goal. Commercial or on-farm feed for poultry are usually presented in the form of pellets, mash or crumble feed. There exists an abundance of published data supporting the superiority of pelleted diets over mash diets. This has been variously observed in the ability of pelleted diets to improve growth rate, FCR, feed intake and dressing percentages of broilers. The quality of pellet offered constitutes a major factor in ensuring improved productivity. Although mash diet is cheaper to produce, studies have shown that it is often not too palatable to broiler birds when compared with pellets. The choice of the type of feed to be adopted therefore depends on the production objectives of the farmer and the prevailing economic conditions. Cost effective pelleting and improvement in pellet quality can therefore offer a viable means for a wholesome broiler production especially in developing countries. [ABSTRACT FROM AUTHOR]

Fibrosis results from the excessive production of extracellular matrix proteins by myofibroblasts. It has recently been reported that in the heart, myofibroblasts develop chondrocyte-like properties following myocardial infarction as fibrosis progresses and tissues stiffen. However, the nature of these chondrocyte-like myofibroblasts remains unclear. In this study, we found that the expression of the proline- and arginine-rich end leucine-rich repeat protein (PRELP) was upregulated in hearts and livers stiffened by fibrosis with chronic inflammation. Moreover, we established that Prelp was specifically expressed in chondrocyte-like myofibroblasts. Prelp expression was found to be regulated by the transcription factor SOX9, and in cardiac and liver myofibroblasts, Prelp -knockdown was observed to reduce collagen expression. These findings reveal that PRELP is specifically expressed in chondrocyte-like myofibroblasts and that it promotes collagen production. PRELP could thus serve as a novel therapeutic target for treating fibrosis. [Display omitted] • Prelp is upregulated in chronically inflamed stiffened fibrotic hearts and livers. • PRELP is specifically expressed in chondrocyte-like myofibroblasts. • PRELP promotes collagen expression in chondrocyte-like myofibroblasts. • Chondrocyte-like myofibroblasts appear in stiffened fibrotic hearts and livers. • SOX9 regulates the expression of Prelp mRNA in chondrocyte-like myofibroblasts. [ABSTRACT FROM AUTHOR]

Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis. [ABSTRACT FROM AUTHOR]

Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway. [Display omitted] • MSC-sEV suppresses LSEC angiogenesis and alleviates MASH in mice. • MSC-sEV-transferred USP9X is responsible for reducing LSEC angiogenesis. • USP9X inhibits LSEC angiogenesis via IκBα/NF-κB/Ang-2 pathway. [ABSTRACT FROM AUTHOR]

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents the most frequent cause of hepatic disorder, and its progressive form defined as Metabolic Dysfunction-Associated Steatohepatitis (MASH) contributes to the development of fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Today effective therapeutic strategies addressing MASH-related comorbidities, inflammation, and fibrosis are needed. The fibroblast growth factor (FGF) 19 and 21 and their fibroblast growth factor receptor/β-Klotho (KLB) complexes have recently emerged as promising druggable targets for MASLD. However, less is known regarding the causative association between KLB activity and advanced stages of liver disease. In the present narrative review, we aimed to provide an up-to-date picture of the role of the KLB co-receptor in MASLD development and progression. We performed a detailed analysis of recently published preclinical and clinical data to decipher the molecular mechanisms underlying KLB function and to correlate the presence of inherited or acquired KLB aberrancies with the predisposition towards MASLD. Moreover, we described ongoing clinical trials evaluating the therapeutic approaches targeting FGF19–21/FGFR/KLB in patients with MASLD and discussed the challenges related to their use. We furtherly described that KLB exhibits protective effects against metabolic disorders by acting in an FGF-dependent and independent manner thus triggering the hypothesis that KLB soluble forms may play a critical role in preserving liver health. Therefore, targeting KLB may provide promising strategies for treating MASLD, as supported by experimental evidence and ongoing clinical trials. [Display omitted] • MASLD is a multisystem disease with a scarcity of approved pharmacotherapies. • FGF19–21/FGFR/KLB and bile acid regulation is crucial in MASLD pathogenesis. • KLB protects against metabolic disorders and liver injury in models of MASLD. • FGF21 and FGF19 analogs improve liver damage and metabolism in patients with MASH. • Targeting the FGFR/KLB pathway has emerged as a promising therapy for MASLD. [ABSTRACT FROM AUTHOR]

• Precision medicine in MASLD predominantly focuses on genetics and diet. • Gut microbiota are important disease drivers that interact with genetics and diet. • Dietary substrates induce gut microbiota imbalances, influencing MASLD pathogenesis. • Crosstalk between microbes, diet, and genetics in MASLD is not fully understood. • Mechanistic insight is required to support the use of precision medicine in MASLD. Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH. [ABSTRACT FROM AUTHOR]

Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern with significant implications for oncogenesis. This review synthesizes current evidence on the association between MASLD and cancer risk, highlighting its role as a risk factor for both intrahepatic and extrahepatic malignancies. MASLD is increasingly recognized as a major cause of hepatocellular carcinoma (HCC), with its incidence rising in parallel with the prevalence of metabolic dysfunction. Furthermore, MASLD is associated with an elevated risk of various gastrointestinal cancers, including colorectal, esophageal, stomach, and pancreatic cancers. Beyond the digestive tract, evidence suggests that MASLD may also contribute to an increased risk of other cancers such as breast, prostate, thyroid, gynecological, renal and lung cancers. Understanding the mechanisms underlying these associations and the impact of MASLD on cancer risk is crucial for developing targeted screening and prevention strategies. • Metabolic- dysfunction associated liver disease (MASLD) is a significant risk factor for intrahepatic and extrahepatic cancers. • The incidence of MASLD-related hepatocellular carcinoma (HCC) is increasing and becoming the predominant HCC cause even in non-cirrhotics. • MASLD is associated with increased risk for gastrointestinal cancers (e.g. colorectal, esophageal, stomach, and pancreatic). • MASLD has been linked to an increased risk of extraintestinal cancers. [ABSTRACT FROM AUTHOR]

The document is a corrigendum published on October 16, 2024, in the journal "Frontiers in Cell & Developmental Biology." It addresses errors in the Conflict of Interest statement of an article on pyroptosis and gasdermins in metabolic dysfunction-associated steatohepatitis. The correction includes the inclusion of author Ariel E. Feldstein in the Conflict of Interest statement. The document emphasizes that the scientific conclusions of the original article remain unchanged despite the error. [Extracted from the article]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort. We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies. Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0–2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • ·GDF15 is a member of the TGFβ superfamily that regulates metabolism through GFRAL. • ·GDF15 plays a protective role in MASH and hepatic fibrosis. • ·GDF15 aggravates the progression of HCC. • ·The expression of GDF15 is associated with many other liver diseases. Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-β (TGFβ) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases. [ABSTRACT FROM AUTHOR]

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of diseases ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and eventually cirrhosis and liver cancer. • A genetic algorithm was applied to a cohort of 541 patients with biopsy-proven MASLD to classify them into two subgroups: M subtype (associated with the MAT1A mouse model) and non-M subtype. • The M subtype cohort was found to have significantly different metabolic profiles than the non-M subtype cohort, which may have important implications for the diagnosis and treatment of diseases associated with this subtype. • The pygenmet package was developed to apply genetic algorithms to metabolic data and select patients with a specific phenotype. • Genetic algorithms can be used to match a patient's genetic profile to others with similar metabolic characteristics, identify disease-causing genes and genetic markers, and develop personalized treatments. We previously identified subsets of patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD) with different metabolic phenotypes. Here, we aimed to refine this classification based on genetic algorithms implemented in a Python package. The use of these genetic algorithms can help scientists to solve problems which cannot be solved with other methods. We present this package and its capabilities with specific problems. The name, PyGenMet, comes from its main goal, solving problems in Python with Genetic Algorithms and Metabolomics data. We collected serum from methionine adenosyltransferase 1a knockout (Mat1a-KO) mice, which have chronically low level of hepatic S-adenosylmethionine (SAMe) and the metabolomes of all samples were determined. We also analyzed serum metabolomes of 541 patients with biopsy proven MASLD (182 with simple steatosis and 359 with metabolic (dysfunction)-associated steatohepatitis or MASH) and compared them with the serum metabolomes of this specific MASLD mouse model using Genetic Algorithms in order to select patients with a specific phenotype. By applying genetic algorithms, we have found a subgroup of patients with a lipid profile similar to that observed in the mouse model. When analyzing the two groups of patients, we have seen that patients with a lipid profile reflecting the mouse model characteristics show significant differences in lipoproteins, especially in LDL-4, LDL-5, and LDL-6 associated with atherogenic risk. The results show that the application of genetic algorithms to subclassify patients with MASLD (or other metabolic disease) give consistent results and are a good approximation for the treatment of large volumes of data such as those from omics sciences and patient classification. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction associated steatotic liver disease (MASLD), is closely associated with type 2 diabetes (T2D). Our aim was to estimate the most recent global prevalence of NAFLD/MASLD, nonalcoholic steatohepatitis (NASH), now known as metabolic dysfunction associated steatohepatitis (MASH), advanced fibrosis, and mortality among patients with T2D. We systematically searched PubMed and Ovid MEDLINE for terms including NAFLD, NASH, and T2D published in 1990–2023 according to PRISMA. The meta-analysis was conducted using a random-effects model. Assessment of bias risk used the Joanna Briggs Institute appraisal tool. From 3134 studies included in the initial search, 123 studies (N = 2,224,144 patients with T2D) were eligible. Another 12 studies (N = 2733 T2D patients with liver biopsy) were eligible for histologic assessments. The global pooled prevalence of NAFLD/MASLD among patients with T2D was 65.33% (95% confidence interval, 62.35%–68.18%). This prevalence increased from 55.86% (42.38%–68.53%) in 1990–2004 to 68.81% (63.41%–73.74%) in 2016–2021 (P =.073). The highest NAFLD/MASLD prevalence among T2D patients was observed in Eastern Europe (80.62%, 75.72%–84.73%), followed by the Middle East (71.24%, 62.22%–78.84%), and was lowest in Africa (53.10%, 26.05%–78.44%). Among patients with liver biopsy data, the global pooled prevalence of NASH/MASH, significant fibrosis, and advanced fibrosis was 66.44% (56.61%–75.02%), 40.78% (24.24%–59.70%), and 15.49% (6.99%–30.99%), respectively. The pooled all-cause mortality was 16.79 per 1000 person-years (PY) (10.64–26.40), 4.19 per 1000 PY (1.34–7.05) for cardiac-specific mortality; 6.10 per 1000 PY (0.78–4.88) for extrahepatic cancer-specific mortality; and 2.15 per 1000 PY (0.00–2.21) for liver-specific mortality. The prevalence of NAFLD/MASLD among T2D is high and growing. The majority of NAFLD/MASLD patients with T2D have NASH/MASH, and a significant proportion have advanced fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Obesity and fatty liver diseases—metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)—affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2 −/− and Aldh2 −/− Sptbn1 +/− mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2 −/− and Aldh2 −/− Sptbn1 +/− mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target. [Display omitted] • ALDH2 and SPTBN1 alterations lead to obesity, MASH, and HCC • Disruption of TGF-β signaling by toxic cleavage of Smad3 adaptor SPTBN1 • SPTBN1 is a potential therapeutic target for MASH and HCC Yang et al. reveal how accumulated endogenous toxins—aldehydes—produced by a Western diet disrupts TGF-β signaling, leading to MASLD/MASH and cancer. Targeting SPTBN1 (SMAD3 adaptor) blocks aldehyde-induced SPTBN1 cleavage and adduct formation, offering a non-toxic approach to achieving beneficial responses in patients with MetS, MASH, and cancer. [ABSTRACT FROM AUTHOR]

The article focuses on the potential of survodutide, a novel GCGR/GLP-1RA dual agonist, in treating obesity and metabolic dysfunction-associated steatohepatitis (MASH), as presented at the EASD (European Association for the Study of Diabetes) 2024. It details results from two phase 2 clinical trials, which showed that survodutide led to significant weight loss and improvements in liver health for participants with obesity and MASH.

[Display omitted] The normal liver has an extraordinary capacity of regeneration. However, this capacity is significantly impaired in steatotic livers. Emerging evidence indicates that metabolic dysfunction associated steatotic liver disease (MASLD) and liver regeneration share several key mechanisms. Some classical liver regeneration pathways, such as HGF/c-Met, EGFR, Wnt/β-catenin and Hippo/YAP-TAZ are affected in MASLD. Some recently established therapeutic targets for MASH such as the Thyroid Hormone (TH) receptors, Glucagon-like protein 1 (GLP1), Farnesoid X receptor (FXR), Peroxisome Proliferator-Activated Receptors (PPARs) as well as Fibroblast Growth Factor 21 (FGF21) are also reported to affect hepatocyte proliferation. With this review we aim to provide insight into common molecular pathways, that may ultimately enable therapeutic strategies that synergistically ameliorate steatohepatitis and improve the regenerating capacity of steatotic livers. With the recent rise of prolonged ex-vivo normothermic liver perfusion prior to organ transplantation such treatment is no longer restricted to patients undergoing major liver resection or transplantation, but may eventually include perfused (steatotic) donor livers or even liver segments, opening hitherto unexplored therapeutic avenues. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), encompasses a progressive spectrum of liver conditions, ranging from steatosis to metabolic dysfunction-associated steatohepatitis, characterised by hepatocellular death and inflammation, potentially progressing to cirrhosis and/or liver cancer. In both experimental and human MASLD, necroptosis-a regulated immunogenic necrotic cell death pathway-is triggered, yet its exact role in disease pathogenesis remains unclear. Noteworthy, necroptosis-related signalling pathways are emerging as key players in metabolic reprogramming, including lipid and mitochondrial metabolism. Additionally, metabolic dysregulation is a well-established contributor to MASLD development and progression. This review explores the intricate interplay between cell metabolism and necroptosis regulation and its impact on MASLD pathogenesis. Understanding these cellular events may offer new insights into the complexity of MASLD pathophysiology, potentially uncovering therapeutic opportunities and unforeseen metabolic consequences of targeting necroptosis. [Display omitted] • A bidirectional axis of regulation between necroptosis and metabolism is emerging. • Necroptosis impacts mitochondrial and lipid metabolism, and the mTORC pathway. • Metabolic imbalance and liver damage are key factors in MASLD pathogenesis. • Few studies have explored the effects of different types of hepatic cell death on metabolism. • Exploring the interplay metabolism-necroptosis may reveal therapeutic targets in MASLD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In metabolic dysfunction-associated steatohepatitis (MASH)-related HCC, cellular redox imbalance from metabolic disturbances leads to dysregulation of the α1-subunit of the Na/K-ATPase (ATP1A1) signalosome. We have recently reported that the normalization of this pathway exhibited tumor suppressor activity in MASH-HCC. We hypothesized that dysregulated signaling from the ATP1A1, mediated by cellular metabolic stress, promotes aberrant epigenetic modifications including abnormal post-translational histone modifications and dysfunctional autophagic activity, leading to HCC development and progression. Increased H3K9 acetylation (H3K9ac) and H3K9 tri-methylation (H3K9me3) were observed in human HCC cell lines, HCC-xenograft and MASH-HCC mouse models, and epigenetic changes were associated with decreased cell autophagy in HCC cell lines. Inhibition of the pro-autophagic transcription factor FoxO1 was associated with elevated protein carbonylation and decreased levels of reduced glutathione (GSH). In contrast, normalization of the ATP1A1 signaling significantly decreased H3K9ac and H3K9me3, in vitro and in vivo, with concomitant nuclear localization of FoxO1, heightening cell autophagy and cancer-cell apoptotic activities in treated HCC cell lines. Our results showed the critical role of the ATP1A1 signalosome in HCC development and progression through epigenetic modifications and impaired cell autophagy activity, highlighting the importance of the ATP1A1 pathway as a potential therapeutic target for HCC.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.

Introduction. Recent studies have shown the benefits of phytolytic enzymes to prepare grain wort in ethanol production. However, there is a lack of data on the effect of phytases and their amount on the conversion of grain polymers, the ionic composition of wort and mash, and the efficiency of yeast generation and ethanol fermentation. Study objects and methods. Wheat and corn wort samples were treated with a complex of hydrolases, including phytases. Capillary electrophoresis determined the ionic composition of wort and mash. Gas chromatography measured the content of volatile metabolites. Results and discussion. The key enzymes were phytases and proteases. They improved the conversion of grain polymers and stimulated the growth and metabolism of yeast cells. Their synergism enriched the wort with assimilable nitrogen, phosphorus, and other valuable minerals. In addition, it intensified the growth of the Saccharomyces cerevisiae yeast, increased the rate of carbohydrate consumption, and reduced the formation of side metabolites 1.7–1.9 times, mainly due to higher and aromatic alcohols. The concentration of phosphates remained practically unchanged during the fermentation of grain wort treated with phytases. However, by the end of fermentation, it was 2.4–5.1 times higher than in the mash samples without phytolytic treatment. Finally, we identified a complex of enzymes and optimal amounts of phytases that have a stimulating effect on ethanol fermentation. Conclusion. Phytases, whether used individually or together with proteases, enriched grain wort with soluble macro- and microelements, improved yeast metabolism, directed ethanol synthesis, and decreased the formation of fermentation by-products.

Clinical observations indicate that during critical care at the hospitals, a patient's sleep positioning and motion have a significant effect on recovery rate. Unfortunately, there is no formal medical protocol to record, quantify, and analyze motion of patients. There are very few clinical studies that use manual analysis of sleep poses and motion recordings to support medical benefits of patient positioning and motion monitoring. Manual processes do not scale, are prone to human errors, and put strain on an already taxed healthcare workforce. This study introduces multimodal, multiview motion analysis and summarization for healthcare (MASH). MASH is an autonomous system, which addresses these issues by monitoring healthcare environments and enabling the recording and analysis of patient sleep-pose patterns. MASH uses three RGB-D cameras to monitor patients in a medical intensive care unit (ICU) room. The proposed algorithms estimate pose direction at different temporal resolutions and use keyframes to efficiently represent pose transition dynamics. MASH combines deep features computed from the data with a modified version of hidden Markov model (HMM) to flexibly model pose duration and summarize patient motion. The performance is evaluated in ideal (BC: Bright and clear/occlusion-free) and natural (DO: Dark and occluded) scenarios at two motion resolutions and in two environments: A mock-up and a medical ICU. The usage of deep features is evaluated and their performance compared with engineered features. Experimental results using deep features in DO scenes increase performance from 86.7% to 93.6%, while matching the classification performance of engineered features in BC scenes. The performance of MASH is compared with HMM and C3D. The overall overtime tracing and summarization error rate across all methods increased when transitioning from the mock-up to the the medical ICU data. The proposed keyframe estimation helps achieve a 78% transition classification accuracy.

Background: Fatty acid esters of hydroxy fatty acids (FAHFAs) present potential beneficial effects that could offer valuable insights into metabolic and inflammatory diseases. However, few FAHFAs have been studied, and their role is unclear., Aims: To assess FAHFA levels in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) associated with morbid obesity (MO) to explore the potential significance of FAHFAs under these conditions., Methods: Using ultra-precise liquid chromatography, FAHFA serum levels were measured in 219 women, including 53 with normal weight (NW) and 166 with MO. The MO group was classified by histological diagnosis into 35 normal liver (NL), 38 simple steatosis (SS) and 93 metabolic dysfunction-associated steatohepatitis (MASH) groups., Results: Thirty-two FAHFA isoforms from 11 families were identified. Most FAHFAs presented low levels in MO, but tLAHOAs, LAHOA-1 and OAHOA-1 increased. In MASLD, elevated tLAHPO, LAHPO-2, PAHLA-3 and PAHLA-4 levels were observed. In MASH, increased POHLA-1, tLAHPOs, LAHPO-2 and LAHLA-3 and decreased PAHSA-1, tOAHOAs, OAHSA-2 and OAHSA-3 levels were reported., Conclusion: This study reveals novel insights into FAHFAs in a cohort of women with MO with MASLD. In MASLD, we reported only increased levels of certain FAHFAs. In MASH, we found a different profile that could be characteristic., Competing Interests: Conflict of interest None, (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH., Methods: The IEC-specific Ticam1 knockout (Ticam1 ΔIEC ) mice and the control (Ticam1 fl/fl ) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration., Results: The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed Ticam1 ΔIEC mice, which had improved MASH disorders compared with Ticam1 fl/fl . Additionally, HFD-fed Ticam1 ΔIEC mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of Akkermansia muciniphila. We proved that Akkermansia muciniphila encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-Ticam1 ΔIEC mice., Conclusion: Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of Akkermansia muciniphila, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ling Yang reports financial support was provided by National Natural Science Foundation of China. Ling Yang reports financial support was provided by Ministry of Science and Technology of the People's Republic of China. Ling Yang reports financial support was provided by Natural Science Foundation of Hubei Province. Weijun Wang reports financial support was provided by National Natural Science Foundation of China. Huikuan Chu reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from Metabolic dysfunction-associated steatotic liver (MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. We compared transcriptome and chromatin accessibility of human HSCs from NORMAL, MASL, and MASH livers at single cell resolution. We aimed to identify genes that are upregulated in activated HSCs and to determine which of these genes are key in the pathogenesis of MASH fibrosis., Methods: 18 human livers were profiled using single-nucleus (sn)RNA-seq and snATAC-seq. High priority targets were identified, then tested in 2D human HSC cultures, 3D human liver spheroids, and HSC-specific gene knockout mice., Results: MASH-enriched activated (A) HSC subclusters are the major source of extracellular matrix proteins. We identified a set of concurrently upregulated and more accessible core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive activation of (A) HSC subclusters. Expression of these genes was regulated via crosstalk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors. The pathological relevance of the selected targets, such as SERPINE1 (PAI-1), was demonstrated using dsiRNA-based HSC-specific gene knockdown or pharmacological inhibition of PAI-1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice., Conclusion: This study identified novel gene targets and regulatory mechanisms underlying activation of MASH fibrogenic HSCs and demonstrated that genetic or pharmacological inhibition of select genes suppressed liver fibrosis., Impact and Implications: Here we present snRNA-seq and snATAC-seq analysis of human HSCs from NORMAL, MASL, and MASH livers. We identified additional subclusters that were not detected by previous studies and characterized the mechanism by which HSCs activate in the MASH livers, including the transcriptional machinery that activates HSCs into myofibroblasts. For the first time, we described the pathogenic role of activated HSC-derived PAI-1 (a product of SERPINE1 gene) in the development of MASH liver fibrosis. Targeting of RUNX1/2-SERPINE1 axis may provide a novel strategy for treatment of liver fibrosis in patients., Competing Interests: Declaration of Competing Interest Nothing to declare, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mice lacking monoacylglycerol acyltransferase 2 (mMGAT2 1 ) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated humanized hMOGAT2 mice (HuMgat2) for use in pre-clinical studies testing the efficacy of hMOGAT2 inhibitors for treating MASLD/MASH. HuMgat2 mice developed MASH when fed a steatotic diet. Computer-aided histology revealed the presence of hepatocyte cell ballooning, immune cell infiltration, and fibrosis. Hepatocytes accumulated Mallory-Denk bodies containing phosphorylated p62/sequestosome-1-ubiquintinated protein aggregates likely caused by defects in autophagy. Metainflammation and apoptotic cell death were seen in the livers of HuMgat2 mice. Treating HuMgat2 mice with elafibranor reduced several MASH phenotypes. RNASeq analysis predicted changes in bile acid transporter expression that correlated with altered bile acid metabolism indicative of cholestasis. Our results suggest that HuMgat2 mice will serve as a pre-clinical model for testing hMOGAT2 inhibitor efficacy and toxicity and allow for the study of hMOGAT2 in the context of MASH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC 50 value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Liver fibrosis, an abnormal accumulation of collagen fibers in the liver, is caused due to several chronic liver diseases including viral hepatitis, alcoholic steatohepatitis, and metabolic dysfunction-associated steatohepatitis. Among the various symptoms of chronic hepatitis, liver fibrosis is the most crucial factor in determining patient prognosis. Extensive liver fibrosis leads to cirrhosis and liver cancer and shortens the lifespans of patients. However, no drug is currently approved for the treatment of liver fibrosis. Therefore, the identification of molecular mechanisms and druggable targets of liver fibrosis is urgently needed. Interleukin-11 is a member of the interleukin-6 family of inflammatory cytokines that is involved in multiple processes of inflammation and tissue repair. Recent reports also suggest the pro-fibrogenic function of interleukin-11 in various organs. In this study, we examined the fibrogenic potential of interleukin-11 in the liver using a choline-deficient, amino acid-defined high-fat diet, a mouse model of metabolic dysfunction-associated steatohepatitis that rapidly develops liver fibrosis. Although interleukin-11 was specifically upregulated in the liver in this pathological model, the loss of interleukin-11 signaling played minor roles in liver injury, inflammation, fibrosis, and signal transduction pathways. Our results indicate that the pro-fibrogenic function of interleukin-11 may vary among organs and disease etiologies., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in children. We hypothesized environmental toxins could drive progression to metabolic dysfunction-associated steatohepatitis (MASH), and assayed serum toxins and metabolites in children with histologically characterized MASLD/MASH., Methods: Environmental chemicals, common in household items, perfluoroalkyl substances (PFAS), polybrominated flame retardants (polybrominated diphenyl ethers [PBDEs]), and metabolic profiles were assayed in children enrolled in the multicenter NASH Clinical Research Network Pediatric Database 2. Mixture models, using repeated holdout weighted quantile sum regression (WQS rh ) were run in addition to single chemical/metabolite logistic regression. For metabolomic analyses, random subset version of WQS rh was used for the large number of predictors versus participants. Nominal and false discovery rate (FDR) p-values (two-sided) were computed., Results: Four hundred and thirty-five children distributed across MASH (n = 293) and MASLD (n = 142), with 304 (69.9%) males. Mean (standard deviation) for Nonalcoholic Steatohepatitis Score (NAS) and alanine aminotransferase (ALT) for MASLD were 3.1 (1.0), 67.9 (43.4), and for MASH 4.2 (1.4), 144 (121). There was an inverse association between PFAS/PBDE mixture and MASH versus MASLD, lobular inflammation (p = 0.026), NAS (p = 0.009, FDR p = 0.04), and log-transformed ALT (p = 0.005, FDR p = 0.025) driven by perfluorohexane sulfonate (PFHXS). Metabolites from positive hydrophilic interaction liquid chromatography mode, biliverdin (p = 0.002) and 1-methylhistidine (associated with meat ingestion, p = 0.02) and reverse phase negative mode, hippuric acid (solvent exposure, p = 0.022) significantly associated with MASH., Conclusions: Significant negative PFAS/PBDE mixture effect and odds of MASH were dominated by PHFXS. Several metabolites are significantly associated with MASH which inform mechanistic pathways and could drive key therapeutic and diagnostic strategies in children., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: Liver tissue and plasma samples were collected during liver biopsy to diagnose MASLD. Untargeted proteomics was performed on 64 patients., Results: Twenty plasma proteins were up- or downregulated in patients with MASH compared with those without MASH. The potential biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These 10 plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values., Conclusion: The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection., (© 2024 Wiley‐VCH GmbH.)

The current diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is suboptimal. Here, we recruited 700 individuals, including 184 from Hong Kong as a discovery cohort and 516 from San Diego, Wenzhou, and Hong Kong as three validation cohorts. A panel of 3 parameters (C-X-C motif chemokine ligand 10 [CXCL10], cytokeratin 18 fragments M30 [CK-18], and adjusted body mass index [BMI]) was formulated (termed N3-MASH), which discriminated patients with MASLD from healthy controls with an area under the receiver operating characteristic (AUROC) of 0.954. Among patients with MASLD, N3-MASH could identify patients with MASH with an AUROC of 0.823, achieving 90.0% specificity, 62.9% sensitivity, and 88.6% positive predictive value. The diagnostic performance of N3-MASH was confirmed in three validation cohorts with AUROC of 0.802, 0.805, and 0.823, respectively. Additionally, N3-MASH identifies patients with MASH improvement with an AUROC of 0.857. In summary, we developed a robust blood-based panel for the non-invasive diagnosis of MASH, which might help clinicians reduce unnecessary liver biopsies., Competing Interests: Declaration of interests R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc. V.W.-S.W. has served as an advisory board member or consultant for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna and as a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology Limited. V.W.-S.W. serves as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, and TARGET PharmaSolutions and as a speaker for Abbott, AbbVie, Gilead Sciences, and Novo Nordisk. He has received a grant from Gilead Sciences for fatty liver research and is a co-founder of Illuminatio Medical Technology Limited., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background and Aims: Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated., Approach & Results: In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and Elovl5-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. Elovl5 deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in Elovl5-/- mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in Elovl5-/- mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in Elovl5-/- mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes., Conclusion: Enhanced susceptibility to diet-induced MASH and fibrosis in Elovl5-/- mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: The risk of disease progression in MASH increases proportionally to the pathological stage of fibrosis. This latter is evaluated through a semi-quantitative process, which has limited sensitivity in reflecting changes in disease or response to treatment. This study aims to test the clinical impact of Artificial Intelligence (AI) in characterizing liver fibrosis in MASH patients., Methods: The study included 60 patients with clinical pathological diagnosis of MASH. Among these, 17 received a medical treatment and underwent a post-treatment biopsy. For each biopsy (n = 77) a Sirius Red digital slide (SR-WSI) was obtained. AI extracts >30 features from SR-WSI, including estimated collagen area (ECA) and entropy of collagen (EnC)., Results: AI highlighted that different histopathological stages are associated with progressive and significant increase of ECA (F2: 2.6% ± 0.4; F3: 5.7% ± 0.4; F4: 10.9% ± 0.8; p: 0.0001) and EnC (F2: 0.96 ± 0.05; F3: 1.24 ± 0.06; F4: 1.80 ± 0.11, p: 0.0001); disclosed the heterogeneity of fibrosis among pathological homogenous cases; revealed post treatment fibrosis modification in 76% of the cases ( vs 56% detected by histopathology)., Conclusion: AI characterizes the fibrosis process by its true, continuous, and non-categorical nature, thus allowing for better identification of the response to anti-MASH treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Akpinar, Panzeri, De Carlo, Belsito, Durante, Chirico, Lombardi, Fracanzani, Maggioni, Arcari, Roncalli, Terracciano, Inverso, Aghemo, Pugliese, Sironi and Di Tommaso.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as a global health issue. This study examines the role of small RNAs in the spleen of MASH using a non-human primate model. We performed high-throughput small RNA sequencing on spleen tissues from MASH-primates, revealing significant alterations in the expression of small non-coding RNAs, especially miRNAs. Notably, miR-96, miR-182, miR-183, and miR-122 showed differential expression in MASH spleens. Predictive and validation studies have identified potential target genes, such as PTX3 and NFIX, that were significantly dysregulated in spleens of MASH. These findings characterized small RNAs in spleen of MASH and offer a novel insight for further research for MASH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetes mellitus is defined as a group of metabolic diseases characterized by chronic hyperglycemia based on insufficient insulin action. At present, treatment for diabetes aims to prevent micro- and macrovascular complications. Although advances have been made in methods of controlling the risk factors of complications, including blood glucose management, there is still no effective treatment to cure diabetes. This is largely because we do not fully understand what diabetes is. To cure diabetes, it is necessary to elucidate the whole picture of insulin actions including those other than metabolic actions in various tissues and to understand what disorders are caused by its reduction or excess. This article reviews diverse insulin actions in various organs and the effects of their deficiency on diabetes, its complications, and associated diseases., Competing Interests: None, (Copyright © Japan Medical Association.)

Non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a complex multifactorial disease that progresses from steatohepatitis (MASH) to liver cirrhosis and liver cancer. Recent research has revealed that crosstalk between innate immune cells and hepatic parenchymal and non-parenchymal cells is involved in the pathogenesis of liver disease in MASLD/MASH. Of particular importance, novel inflammatory mechanisms, including macrophage diversity, neutrophil NETosis, B-cell biology, auto-reactive T cells, unconventional T cells, and dendritic cell-T cell interactions, are considered key drivers for disease progression. These mechanisms and factors are potential targets for the therapeutic intervention of MASLD/MASH. In this review, we focus on recent discoveries related to liver inflammation and discuss the role of innate immune cell subsets in MASLD/MASH., Competing Interests: T.K. and S.Y. received lecture fees from Gilead Sciences., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic-Dysfunction Associated Steatohepatitis (MASH) are linked to obesity, type 2 diabetes, and metabolic syndrome, increasing liver-related morbidity and cardiovascular risk. Recent therapies, including Resmetirom, FGF21 analogs, and GLP-1 agonists, have shown promise. This network meta-analysis evaluates their comparative efficacy and safety., Methods: A literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library. Included clinical trials addressed MASLD or MASH with Resmetirom, FGF21 analogs, or GLP-1 agonists. Statistical analyses used a random-effects model, calculating mean differences (MD) and relative risks (RR), with heterogeneity assessed using τ 2 , I 2 , and Q statistics., Results: MASH resolution was significantly higher for FGF21 (RR 4.84, 95% CI: 2.59 to 9.03), Resmetirom showed the most significant reduction in MRI-PDFF (MD -18.41, 95% CI: -23.60 to -13.22) and >30% fat reduction (RR 3.56, 95% CI: 2.41 to 5.26). Resmetirom significantly reduced ALT (MD -15.71, 95% CI: -23.30 to -8.13), AST (MD -12.28, 95% CI: -21.07 to -3.49), and GGT (MD -19.56, 95% CI: -34.68 to -4.44). FGF21 and GLP-1 also reduced these markers. Adverse events were significantly higher with Resmetirom (RR 1.47, 95% CI: 1.24 to 1.74), while GLP-1 and FGF21 showed non-significant trends towards increased risk., Conclusions: Resmetirom and FGF21 show promise in treating MASLD and MASH, with Resmetirom particularly effective in reducing liver fat and improving liver enzymes. GLP-1 agonists also show benefits but to a lesser extent. Further long-term studies are needed to validate these findings and assess cost-effectiveness.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis., Methods: Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard., Results: We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies., Conclusions: Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Objective: To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis., Methods: Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq., Results: Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis., Conclusion: This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background and Aim: Following the approval of the first agent for the management of metabolic dysfunction-associated steatohepatitis (MASH), identification of patients with fibrotic MASH (MASH with NAS ≥ 4 and fibrosis stage ≥ 2) is crucial. We assessed the performance of FibroScan-aspartate aminotransferase (AST) score (FAST) for ruling in/out fibrotic MASH., Methods: We searched Medline, Cochrane Library, Web of Science, Scopus, and gray literature sources up to January 11, 2024. Studies were eligible if they assessed the accuracy of FAST score for the detection of fibrotic MASH using biopsy as the reference standard at previously reported thresholds (FAST ≥ 0.67 for ruling-in and ≤ 0.35 for ruling-out fibrotic MASH). We calculated pooled sensitivity and specificity estimates for FAST thresholds alongside 95% confidence intervals following bivariate random- effects models. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework., Results: We included 16 studies with 8838 participants. A FAST score ≥ 0.67 yielded a pooled specificity of 0.87 (0.82-0.90) while a FAST score ≤ 0.35 yielded a summary sensitivity of 0.88 (0.83-0.91). At a prevalence of 30%, the positive predictive value for ruling-in fibrotic MASH was 60% while the negative predictive value for ruling-out the target condition was 91%. AST levels, cirrhosis prevalence, and number of pathologists reviewing biopsies were sources of heterogeneity among studies. The certainty of evidence was low to very low., Conclusions: FAST score can be used as a triage test for ruling out fibrotic MASH. Nevertheless, its low positive predictive value necessitates sequential testing for ruling-in fibrotic MASH., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)