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The clinical application of ferroptosis, characterized by iron‐dependent lipid peroxidation, is limited because of the serious side effects of using toxic‐dose iron. Herein, a polyvalent ferroptosis agonist‐a hypoxia responsive polymer bearing 18‐crown‐6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural "iron pools" of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer‐chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH2) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti‐tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8+ T‐cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer‐hijacking endogenous iron and GSH may offer new therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin–proteasome system is critical in the hypoxia response, but hypoxia‐inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF‐2alpha protein in an ERK1/2‐dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF‐2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF‐2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment. Synopsis: While hypoxia induced by tumor growth is recognized as a key selective pressure in solid cancers, the molecular mechanisms underlying control of HIF signaling remain unclear. This work identifies deubiquitinating enzyme USP33 as regulator of HIF‐2alpha in glioma, shedding new light on the complexities of brain tumor growth. Hypoxia induces deubiquitinase USP33 expression in glioma stem cells (GSCs).USP33 deubiquitinates and stabilizes HIF‐2alpha in GSCs in response to hypoxia.ERK1/2‐mediated phosphorylation of S484 HIF‐2alpha enhances binding to USP33.Depletion of USP33 impairs GSC maintenance and tumor sphere formation in vitro as well as glioblastoma growth in mice. [ABSTRACT FROM AUTHOR]

Hypoxia inactivates hypoxia‐inducible factor (HIF) prolyl 4‐hydroxylases (HIF‐P4Hs), which stabilize HIF and upregulate genes to restore tissue oxygenation. HIF‐P4Hs can also be inhibited by small molecules studied in clinical trials for renal anemia. Knowledge of systemic long‐term inactivation of HIF‐P4Hs is limited but crucial, since HIF overexpression is associated with cancers. We aimed to determine the effects of systemic genetic inhibition of the most abundant isoenzyme HIF prolyl 4‐hydroxylase‐2 (HIF‐P4H‐2)/PHD2/EglN1 on life span and tissue homeostasis in aged mice. Our data showed no difference between wild‐type and HIF‐P4H‐2‐deficient mice in the average age reached. There were several differences, however, in the primary causes of death and comorbidities, the HIF‐P4H‐2‐deficient mice having less inflammation, liver diseases, including cancer, and myocardial infarctions, and not developing anemia. No increased cancer incidence was observed due to HIF‐P4H‐2‐deficiency. These data suggest that chronic inactivation of HIF‐P4H‐2 is not harmful but rather improves the quality of life in senescence. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is an environmental pathogen requiring atmospheric levels of oxygen for optimal growth. Upon inhalation, C. neoformans disseminates to the brain and causes meningoencephalitis. However, the mechanisms by which the pathogen adapts to the low-oxygen environment in the brain have not been investigated. We isolated a C. neoformans strain with a small capsule from a host tissue, although this strain produces large capsules in normoxic conditions. We hypothesize that this difference in capsule size is attributed to hypoxia caused by chronic inflammatory response. This study investigated the effect of hypoxia on virulence factors (including capsule, melanin, urease, and phospholipase) of C. neoformans and conducted transcriptomic analyses of the virulence-associated genes. We found that C. neoformans grew under hypoxic condition, albeit slowly, and that hypoxia may have inhibited the capsule size, melanin production, and phospholipase and urease activities in C. neoformans. [ABSTRACT FROM AUTHOR]

Aims Amyotrophic lateral sclerosis ( ALS) and primary lateral sclerosis ( PLS) are two syndromic variants within the motor neurone disease spectrum. As PLS and most ALS cases are sporadic ( SALS), this limits the availability of cellular models for investigating pathogenic mechanisms and therapeutic targets. The aim of this study was to use gene expression profiling to evaluate fibroblasts as cellular models for SALS and PLS, to establish whether dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish the clinically defined variants of SALS and PLS. Methods Microarray analysis was performed on fibroblast RNA and differentially expressed genes identified. Genes in enriched biological pathways were validated by quantitative PCR and functional assays performed to establish the effect of altered RNA levels on the cellular processes. Results Gene expression profiling demonstrated that whilst there were many differentially expressed genes in common between SALS and PLS fibroblasts, there were many more expressed specifically in the SALS fibroblasts, including those involved in RNA processing and the stress response. Functional analysis of the fibroblasts confirmed a significant decrease in miRNA production and a reduced response to hypoxia in SALS fibroblasts. Furthermore, metabolic gene changes seen in SALS, many of which were also evident in PLS fibroblasts, resulted in dysfunctional cellular respiration. Conclusions The data demonstrate that fibroblasts can act as cellular models for ALS and PLS, by establishing the transcriptional changes in known pathogenic pathways that confer subsequent functional effects and potentially highlight targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

A decrease in oxygenation is a life-threatening situation for most organisms. An evolutionarily conserved efficient and rapid hypoxia response mechanism activated by a hypoxia-inducible transcription factor ( HIF) is present in animals ranging from the simplest multicellular phylum Placozoa to humans. In humans, HIF induces the expression of more than 100 genes that are required to increase oxygen delivery and to reduce oxygen consumption. As its name indicates HIF is found at protein level only in hypoxic cells, whereas in normoxia, it is degraded by the proteasome pathway. Prolyl 4-hydroxylases, enzymes that require oxygen in their reaction, are the cellular oxygen sensors regulating the stability of HIF. In normoxia, 4-hydroxyproline residues formed in the α-subunit of HIF by these enzymes lead to its ubiquitination by the von Hippel- Lindau E3 ubiquitin ligase and immediate destruction in proteasomes thus preventing the formation of a functional HIF αβ dimer. Prolyl 4-hydroxylation is inhibited in hypoxia, facilitating the formation of the HIF dimer and activation of its target genes, such as those for erythropoietin and vascular endothelial growth factor. This review starts with a summary of the molecular and catalytic properties and individual functions of the four HIF prolyl 4-hydroxylase isoenzymes. Induction of the hypoxia response via inhibition of the HIF prolyl 4-hydroxylases may provide a novel therapeutic target in the treatment of hypoxia-associated diseases. The current status of studies aiming at such therapeutic approaches is introduced in the final part of this review. [ABSTRACT FROM AUTHOR]

Abstract: We identified MafG as a protein that interacts with HIF-1α, a key factor in hypoxic response, using the yeast two-hybrid system. Interaction between MafG and HIF-1α was confirmed by surface plasmon resonance and by translocation to the nucleolus with the NoLS signal. A knockdown of MafG reduced erythropoietin (EPO) mRNA levels as well as luciferase reporter activity with the hypoxia response element. The knockdown of MafG did not change total HIF-1α protein, but reduced the accumulation of HIF-1α in the nuclei. These results suggest that MafG regulates the hypoxic response of cells by detaining HIF-1α in the nuclei. Structured summary: MINT-6550898: HIF1A (uniprotkb:Q16665) physically interacts (MI:0218) with MAFG (uniprotkb:Q9BRP3) by two hybrid (MI:0018) MINT-6550966: HIF1A (uniprotkb:Q16665) physically interacts (MI:0218) with HSP90 alpha (uniprotkb:P07900) by surface plasmon resonance (MI:0107) MINT-6550948: HIF1A (uniprotkb:Q16665) physically interacts (MI:0218) with MAFK (uniprotkb:A5PLQ5) by surface plasmon resonance (MI:0107) MINT-6550925: HIF1A (uniprotkb:Q16665) physically interacts (MI:0218) with MAFG (uniprotkb:Q9BRP3) by surface plasmon resonance (MI:0107) MINT-6550912: MAFG (uniprotkb:Q9BRP3) and HIF1A (uniprotkb:Q16665) physically interact (MI:0218) by fluorescence microscopy (MI:0416) MINT-6550980: HIF1A (uniprotkb:Q16665) physically interacts (MI:0218) with HSP90 beta (uniprotkb:P08238) by surface plasmon resonance (MI:0107) [Copyright &y& Elsevier]