bims-oxygme 2025-08-03 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–08–03
seven papers selected by
Onurkan Karabulut, Berkeley City College

Exploring Core Genes Involved in Ischemic Stroke and the Therapeutic Potential of Hyperbaric Oxygen: Insights from Transcriptomic Analysis.
Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.
Deciphering hypoxia's role in hepatocellular carcinoma prognosis with single-cell approaches.
METTL3-mediated MSRB3 m6A modification accelerates hypoxia-induced cardiomyocyte ferroptosis by inhibiting mitochondrial oxidative phosphorylation.
Coupling of the energetic and purinergic activities of ATP in ischemic and hypoxic disease states.
Semaglutide Mitigates Ischemic Brain Injury by Inhibiting Ferroptosis via Modulation of FoXO1 and DRP1 Pathways.
Metabolic Plasticity and Transcriptomic Reprogramming Orchestrate Hypoxia Adaptation in Yak.

Neuromolecular Med. 2025 Jul 26. 27(1): 54

Exploring Core Genes Involved in Ischemic Stroke and the Therapeutic Potential of Hyperbaric Oxygen: Insights from Transcriptomic Analysis.

Yingcun Bao, Xudong Guo, Jinhai Wang, Jihe Kang, Rui Ma, Xiaorong Cheng, Yumei Ma, Yanxia Niu, Wei Zhang, Xiaoling Li.

  Ischemic stroke (IS) is a complex neurological disorder caused by reduced cerebral blood flow, typically resulting in tissue damage due to hypoxia and nutrient deficiency. Hyperbaric oxygen therapy (HBOT) has shown great potential as an adjunctive treatment for IS, though its mechanisms of action are not fully understood. This study employed a middle cerebral artery occlusion (MCAO) mouse model to explore the molecular mechanisms and therapeutic effects of HBOT. Transcriptomic analysis revealed significant changes in gene expression related to ischemia, including differentially expressed genes (DEGs) involved in inflammatory responses, BBB damage, and neural repair, such as Lcn2, Bcl3, Olr1, Pdpn, Gpnmb, and Gfap. HBOT significantly reduced brain damage, modulated the expression of these key genes, and decreased m6A methylation levels, thereby affecting post-transcriptional modifications of RNA. These findings provide new insights into the molecular mechanisms of IS and the development of precise treatment strategies, highlighting the potential of HBOT to reduce brain damage and promote neural repair at the molecular level.

Keywords:  Hyperbaric oxygen therapy; MCAO; Stroke; Transcriptomics; m6A methylation

DOI:  https://doi.org/10.1007/s12017-025-08876-8
Oncol Res. 2025 ;33(8): 1803-1818

Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.

Eduardo Alvarado-Ortiz, Miguel Angel Sarabia-SáNCHEZ.

  The tumor microenvironment (TME) is characterized by a symbiosis between cancer cells and the immune cells. The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors. In response to low oxygen availability, the Hypoxia Inducible Factors (HIF-1/2/3α) act as metabolic mediators, producing extracellular metabolites in the tumor microenvironment that influence the immune cells. The modulation of lactate and adenosine on immune evasion has been widely described; however, under hypoxic conditions, it has been barely addressed. Evidence has demonstrated an interplay between cancer and the immune cells, and the present review explores the findings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context. Moreover, new insights based on systemic oxygen administration are discussed, which might counterbalance the effect mediated by lactate and adenosine, to recover anti-tumor immunity. Thus, the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.

Keywords:  Adenosine; Hypoxia; Hypoxia inducible factors (HIF-1/2/3α); Immune evasion; Lactate; Tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2025.065953
Discov Oncol. 2025 Jul 26. 16(1): 1411

Deciphering hypoxia's role in hepatocellular carcinoma prognosis with single-cell approaches.

Jun Liang, Di Chen, Huiyu Liang.

   BACKGROUND: Hepatocellular carcinoma (HCC), a prevalent and highly lethal malignancy, is notorious for its aggressive nature and inherent tendency to metastasize, posing significant challenges in clinical management and prognosis. Hypoxia, a pivotal characteristic of the tumor microenvironment (TME) in hepatocellular HCC, is intimately linked to disease progression and unfavorable patient outcomes, underscoring its critical role in shaping the malignant behavior of this cancer.
METHODS: Our research leveraged single-cell RNA sequencing technology to dissect the heterogeneity of the HCC TME, focusing on hypoxia-related genes. To probe the effects of hypoxia on HCC invasion, we developed the Cell Hypoxia-Related Prognostic Feature (CHPF). We analyzed transcriptome data from the The Cancer Genome Atlas (TCGA) database and the GSE149614 dataset, employing computational methods such as UMAP, Weighted correlation network analysis (WGCNA), and CellChat to identify hypoxia cells, characterize cell subsets, and elucidate intercellular communications.
RESULTS: Our analysis revealed significant heterogeneity in hypoxia cell populations within the HCC TME, with distinct expression patterns of hypoxia-related genes in neoplastic and immune cells. Our analysis revealed distinct hypoxia subpopulations within HCC, with significant overexpression of genes like MEG3, KLF6 and JUN in hypoxia cells. We identified a unique hypoxia subpopulation with high invasive potential and constructed a prognostic model based on H2-specific transcription factors including LRP10、MED8、NOL10、NOP58 and REXO4. The model demonstrated significant predictive value for lifespan of patients as verified in the TCGA dataset and an external validation group.
CONCLUSION: Key transcription factors like NOP58, MED8 play pivotal roles in hypoxia-induced HCC invasion and metastasis, and a predictive model based on these factors forecasts HCC survival. Our findings provide novel molecular markers and therapeutic targets for HCC, highlighting the importance of considering the hypoxia TME in diagnostic and treatment strategies.

Keywords:  Hepatocellular carcinoma; Hypoxia; Prognostic model; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-03201-y
Int Immunopharmacol. 2025 Jul 30. pii: S1567-5769(25)01258-5. [Epub ahead of print]163 115268

METTL3-mediated MSRB3 m6A modification accelerates hypoxia-induced cardiomyocyte ferroptosis by inhibiting mitochondrial oxidative phosphorylation.

Yansong Li, Jingwen Xia, Yong Wei, Maorong He, Guibin He, Yan Zhu.

   OBJECTIVE: Cardiomyocyte death is a complex biological process involving the interaction of many factors and signaling pathways. In chronic sustained hypoxic environments, cardiomyocytes may die due to insufficient energy supply and increased production of reactive oxygen species (ROS). Myocardial injury caused by chronic sustained hypoxia is a challenging issue with an underlying molecular mechanism that is yet to be clarified. Methionine sulfoxide reductase B3 (MSRB3) protects cells from oxidative damage by catalyzing the stereospecific reduction of methionine-R-sulfoxide residues and reducing intracellular ROS, thus inhibiting cell death. This study aimed to evaluate the role of MSRB3 in regulating chronic sustained hypoxia-induced myocardial injury.
METHODS: Human AC16 cardiomyocytes under hypoxia for 48 h were used for in vitro experiments. Ferroptosis was evaluated using flow cytometry and Western blotting. Mitochondrial oxidative phosphorylation (OXPHOS) was evaluated by measuring the oxygen consumption rate. A murine model of chronic sustained hypoxia-induced myocardial injury was used to assess the effects of MSRB3 on cardiac dysfunction (evaluated via echocardiography) in vivo. Mitochondrial function was evaluated using DHE staining and biochemical analyses. METTL3-mediated N6-methyladenosine (m6A) modification of MSRB3 was evaluated using MeRIP-PCR, a dual-luciferase reporter assay, and RIP-PCR.
RESULTS: MSRB3 modulates OXPHOS, thereby affecting cell viability and mitochondrial function in cardiomyocytes while mitigating chronic sustained hypoxia-induced ferroptosis. Further investigations demonstrated that chronic sustained hypoxia suppresses MSRB3 expression by promoting METTL3-induced m6A modification of MSRB3. Both in vivo and in vitro experiments highlighted the influence of MSRB3 m6A modification and OXPHOS on chronic sustained hypoxia-induced myocardial injury. Notably, treatment with STM2457 inhibited MSRB3 m6A modification, leading to increased MSRB3 expression, which boosted the OXPHOS process, improving cardiomyocyte viability and mitochondrial function under chronic sustained hypoxia conditions, and alleviated cardiac dysfunction and myocardial injury in mice with chronic sustained hypoxia.
CONCLUSION: Our results suggest that MSRB3 plays a critical role in chronic sustained hypoxia-induced cardiomyocyte ferroptosis through mitochondrial OXPHOS modulation.

Keywords:  Chronic sustained hypoxia; Ferroptosis; Methionine sulfoxide reductase B3; Mitochondrial dysfunction; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.intimp.2025.115268
Biosystems. 2025 Jul 23. pii: S0303-2647(25)00154-6. [Epub ahead of print]255 105544

Coupling of the energetic and purinergic activities of ATP in ischemic and hypoxic disease states.

William D Ehringer, Kristyn H Smith.

  Adenosine-5'-triphosphate (ATP) is the single most important molecule in life. It is the universal energy currency of all living things. The energy from ATP is used in the synthesis of RNA/DNA, proteins, and lipids. The energy is used in signal transduction, ion pumping, intracellular and extracellular movement, and heat production. To meet the metabolic demand for ATP, cells utilize oxygen to extract maximal energy from substrates. The dependence on oxygen over the course of evolution allowed cells to grow in size and complexity, but at the same time cells became dependent upon oxygen for cell function and survival. During periods of ischemia or hypoxia, ATP produced by oxidative phosphorylation decreases, cells compensate by increasing glycolytic and substrate level phosphorylation, as well as prioritizing ATP consuming processes. If ischemia or hypoxia continues, extracellular ATP levels increase due to leakage and cell death, and ATP becomes an endogenous ligand that activates purinergic receptors located on cells throughout the body. ATP induces a purinergic response that can vary from cell death to cell proliferation, depending on the concentration of extracellular ATP. The coupling of the energetic and purinergic roles of ATP in ischemia or hypoxia is well illustrated in the leading causes of death in humans in the United States. Intracellular ATP depletion leads to cellular dysfunction and extracellular ATP leads to purinergic mediated responses that attempt to rectify the ischemia or hypoxia issue. Understanding the connections between the energetic and purinergic roles of ATP could be useful in future therapies.

Keywords:  ATP; Disease; Hypoxia; Ischemia; Oxidative phosphorylation; Purinergic

DOI:  https://doi.org/10.1016/j.biosystems.2025.105544
Mol Neurobiol. 2025 Aug 01.

Semaglutide Mitigates Ischemic Brain Injury by Inhibiting Ferroptosis via Modulation of FoXO1 and DRP1 Pathways.

Weihua Wang, Meng Pang, Yifeng Zhang, Shuai Hou, Yulei Xia, Youkui Shi, Xiaojun Zhang, Yanqiang Wang.

  Multiple pathogenic processes contribute to cerebral ischemia-reperfusion injury (CIRI); however, their relative importance and sequence remain unclear, warranting further investigation. Although our previous studies showed that inhibiting ferroptosis mitigates brain damage after ischemic stroke, the crosstalk among intracellular pathways remains poorly understood. The protective effects of semaglutide, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in ischemic stroke have yet to be fully elucidated. In this study, bioinformatics analysis was conducted to predict the potential therapeutic mechanisms of semaglutide in CIRI, highlighting the involvement of the FoXO1-autophagy pathway and mitochondrial dynamics. A rat's middle cerebral artery occlusion/reperfusion (MCAO/R) model was established to validate these predictions. Histopathological examination demonstrated that semaglutide alleviated pathological damage and reduced neuronal apoptosis. Using Western blotting, RT-PCR, immunofluorescence, and ELISA, we assessed key markers-GLP-1R, FoXO1, Beclin1, DRP1, Mfn2, ATP, and ROS-in the ischemic penumbra. The results showed that semaglutide inhibited autophagy (Beclin1), suppressed mitochondrial fission (DRP1), promoted mitochondrial fusion (Mfn2), and improved mitochondrial function, as reflected by increased ATP production and reduced ROS levels. Furthermore, we investigated the involvement of FoXO1 and mitochondrial function in the regulation of ferroptosis. The findings suggest that semaglutide inhibits ferroptosis by activating GLP-1R, thereby modulating the intracellular FoXO1/GPX4 and DRP1/ACSL4 signaling pathways. In summary, semaglutide acts through GLP-1R to regulate FoXO1-mediated autophagy, mitochondrial dynamics, and ferroptosis, as well as to modulate DRP1-dependent mitochondrial fission and ferroptosis. Together, these mechanisms account for its protective effects against ischemic stroke.

Keywords:  Cerebral ischemia/reperfusion injury; DRP1; Ferroptosis; FoXO1; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/s12035-025-05253-1
Animals (Basel). 2025 Jul 15. pii: 2084. [Epub ahead of print]15(14):

Metabolic Plasticity and Transcriptomic Reprogramming Orchestrate Hypoxia Adaptation in Yak.

Ci Huang, Yilie Liao, Wei Peng, Hai Xiang, Hui Wang, Jieqiong Ma, Zhixin Chai, Zhijuan Wu, Binglin Yue, Xin Cai, Jincheng Zhong, Jikun Wang.

  The yak (Bos grunniens) has exceptional hypoxia resilience, making it an ideal model for studying high-altitude adaptation. Here, we investigated the effects of oxygen concentration on yak cardiac fibroblast proliferation and the underlying molecular regulatory pathways using RNA sequencing (RNA-seq) and metabolic analyses. Decreased oxygen levels significantly inhibited cardiac fibroblast proliferation and activity. Intriguingly, while the mitochondrial DNA (mtDNA) content remained stable, we observed coordinated upregulation of mtDNA-encoded oxidative phosphorylation components. Live-cell metabolic assessment further demonstrated that hypoxia led to mitochondrial respiratory inhibition and enhanced glycolysis. RNA-seq analysis identified key hypoxia adaptation genes, including glycolysis regulators (e.g., HK2, TPI1), and hypoxia-inducible factor 1-alpha (HIF-1α), with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighting their involvement in metabolic regulation. The protein-protein interaction network identified three consensus hub genes across five topological algorithms (CCNA2, PLK1, and TP53) that may be involved in hypoxia adaptation. These findings highlight the importance of metabolic reprogramming underlying yak adaptation to hypoxia, providing valuable molecular insights into the mechanisms underlying high-altitude survival.

Keywords:  Bos grunniens; cardiac fibroblasts; gene expression; hypoxia adaptation; transcriptome

DOI:  https://doi.org/10.3390/ani15142084