bims-oxygme 2025-03-23 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–03–23
thirteen papers selected by
Onurkan Karabulut, Berkeley City College

Redefining the role of hypoxia-inducible factors (HIFs) in oxygen homeostasis.
A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.
Small-molecule hypoxia therapy in mitochondrial disease.
Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance.
Hypoxia ameliorates high-fat-diet-induced hepatic lipid accumulation by modulating the HIF2α/PP4C signaling.
Reconstituted High-Density Lipoproteins Rescue Diabetes-Impaired Endothelial Cell Metabolic Reprograming and Angiogenic Responses to Hypoxia.
Integrated analysis of the expression profiles of the lncRNA-miRNA-mRNA ceRNA network in CASMCs under hypoxia and normoxia conditions in yak heart.
Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia.
Knockdown of cytochrome P450 1 A (cyp1a) gene suppresses growth and oxygen tolerance in zebrafish.
Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α.
Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels-Lessons from rat, pig, mouse, and human.
Optimized oxygen therapy improves sleep deprivation-induced cardiac dysfunction through gut microbiota.
A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation.

Commun Biol. 2025 Mar 16. 8(1): 446

Redefining the role of hypoxia-inducible factors (HIFs) in oxygen homeostasis.

Clemente F Arias, Francisco J Acosta, Federica Bertocchini, Cristina Fernández-Arias.

Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell's metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs' activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs' function and underscores the need to explicitly consider the cell's metabolic activity in understanding its responses to changes in oxygen availability.

DOI: https://doi.org/10.1038/s42003-025-07896-1
Bioact Mater. 2025 Jun;48 493-509

A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.

Jeong Min Oh, Tianze Guo, Hydari Masuma Begum, Saci-Elodie Marty, Liang Sha, Cem Kilic, Hao Zhou, Yali Dou, Keyue Shen.

  Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors.

Keywords:  Hypoxia; Metabolic rewiring; Metabolism-targeting therapy; Tumor heterogeneity; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.030
Cell. 2025 Mar 20. pii: S0092-8674(25)00207-7. [Epub ahead of print]188(6): 1462-1465

Small-molecule hypoxia therapy in mitochondrial disease.

Marni J Falk.

In this issue of Cell, Blume et al. provide compelling rationale for pursuing pharmacologic optimization of a small-molecule "HypoxyStat," which left-shifts the oxyhemoglobin dissociation curve in red blood cells in an attempt to induce an effective and sustained reduction of chronic tissue hyperoxia in primary mitochondrial disease (PMD) and was well-tolerated and effective for both pre-symptomatic and advanced disease treatment to extend survival and improve neurologic outcomes in a mouse model of Leigh syndrome spectrum.

DOI: https://doi.org/10.1016/j.cell.2025.02.019
J Hematol Oncol. 2025 Mar 18. 18(1): 32

Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance.

Tongxuan Shang, Ziqi Jia, Jiayi Li, Heng Cao, Hengyi Xu, Lin Cong, Dongxu Ma, Xiang Wang, Jiaqi Liu.

  In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.

Keywords:  Cancer; Cancer stem cell; Drug resistance; Hypoxia

DOI:  https://doi.org/10.1186/s13045-025-01684-4
Cell Signal. 2025 Mar 18. pii: S0898-6568(25)00164-0. [Epub ahead of print] 111751

Hypoxia ameliorates high-fat-diet-induced hepatic lipid accumulation by modulating the HIF2α/PP4C signaling.

Zhe Liu, Jing Hou, MeiYuan Tian, YaoGang Zhang, DengLiang Huang, Na Zhao, Yanyan Ma, Sen Cui.

  Hepatic lipid accumulation is a hallmark of metabolically associated fatty liver disease (MAFLD), which contributes to the progression of cirrhosis and even hepatoma. However, the underlying mechanisms remain poorly understood. Protein phosphatase 4C (PP4C) is an important enzyme that exists widely in the body and participates in cell metabolism. Hypoxia can affect the development of metabolic diseases. In this study, we investigated the role of PP4C in hepatic lipid metabolism under hypoxia in vivo and in vitro. Hypoxia-inducible factor 2α (HIF2α), PP4C, phosphorylated AU-rich element RNA-binding factor 1(pAUF1), acetyl-CoA carboxylase 1 (ACC1), and carnitine palmitoyl transferase-1 (CPT1) were analyzed via western blotting and immunofluorescence. The mechanism by which PP4C affects hepatic lipid accumulation under hypoxia was evaluated in stable transfected cell lines. Compared with those in the 2200 m HFD group, body weight, triglyceride (TG), total cholesterol (TC), amino alanine transferase (ALT), aspartate transaminase (AST), and lipid accumulation were lower in the 4500 m HFD group (P < 0.05). Compared with those in the 4500 m ND group, ACC1 and PP4C levels were lower than in the 4500 m HFD group, but HIF2α, pAUF1, and CPT1 levels were greater (P < 0.05). Knockdown of HIF2α prevented the hypoxia-induced reduction of PP4C, confirming the regulatory role of the HIF2α-PP4C axis in hepatic lipid metabolism. PP4C could affect the phosphorylation and expression localization of AU-rich element RNA-binding factor 1 (AUF1). PP4C enhanced lipid accumulation by reducing pAUF1, while the knockdown of PP4C had the opposite effect; pAUF1 had no change. Compared with those in the control group, ACC1 levels were decreased and CPT1 levels were increased in the AUF1 overexpression group, whereas ACC1 and CPT1 levels were not altered in the AUF1 knockdown group (P < 0.05). In conclusion, hypoxia might improve lipid accumulation by downregulating PP4C via HIF2a. PP4C is involved in hepatic lipid metabolism by regulating AUF1 phosphorylation under different oxygen concentrations. PP4C might be a promising target for treating hepatic lipid accumulation.

Keywords:  AU-rich element RNA-binding factor 1; Hepatic lipid metabolism; Hypoxia; Hypoxia-inducible factor 2α; Protein phosphatase 4C

DOI:  https://doi.org/10.1016/j.cellsig.2025.111751
Arterioscler Thromb Vasc Biol. 2025 Mar 20.

Reconstituted High-Density Lipoproteins Rescue Diabetes-Impaired Endothelial Cell Metabolic Reprograming and Angiogenic Responses to Hypoxia.

Khalia R Primer, Joanne T M Tan, Lauren Sandeman, Victoria A Nankivell, Liam G Stretton, Emma L Solly, Peter J Psaltis, Christina A Bursill.

   BACKGROUND: Impaired angiogenic responses to ischemia underlie diabetic vascular complications. Reconstituted high-density lipoproteins (rHDLs) have proangiogenic effects in diabetes. The PDK4 (pyruvate dehydrogenase kinase 4)/PDC (pyruvate dehydrogenase complex) axis is an oxygen-conserving mechanism that preserves endothelial cell function in hypoxia. We aimed to determine the role of the PDK4/PDC axis in angiogenesis, the effect of diabetes on its regulation in response to ischemia, and the proangiogenic properties of rHDL.
METHODS: Expression of PDK4 and phosphorylated PDC (pPDC) were measured in PBS- or rHDL-treated wounds of nondiabetic and streptozotocin-induced diabetic mice and PBS- or rHDL-treated endothelial cells exposed to glucose and hypoxia. The importance of PDK4 in the action of rHDL was determined by siRNA knockdown in vitro and PDK4 inhibitor in vivo. Chromatin immunoprecipitation assay was performed to identify the mechanism for PDK4 induction by rHDL.
RESULTS: PDK4 and pPDC were elevated early (24 hours) post-induction of wound ischemia in nondiabetic wounds, which did not occur in diabetic mice. Topical rHDL rescued this impairment, enhancing PDK4 (68%; P=0.0041) and pPDC (165%; P=0.029) in diabetic wounds. Wound neovascularization (62%; P<0.05) and closure (154%; P<0.001) were increased in diabetic rHDL-treated wounds. In vitro, PDK4 and pPDC levels were increased with hypoxia (65%, P=0.043 and 64%, P=0.026, respectively). High glucose did not elicit a further stepwise induction in PDK4/pPDC, with aberrant increases in mitochondrial respiration (19%; P=0.026), and impaired angiogenic functions. Importantly, rHDL increased PDK4 and pPDC 2-fold, returning mitochondrial respiration and angiogenic functions to normal glucose levels. PDK4 inhibition ameliorated the proangiogenic effects of rHDL. rHDL increased FOXO1 (forkhead box O1) binding to the PDK4 promoter and suppressed FOXO1 phosphorylation, presenting FOXO1 as a mechanism for rHDL-mediated induction of PDK4.
CONCLUSIONS: The PDK4/PDC axis response to ischemia is impaired in diabetes and is important for the proangiogenic effects of rHDL.

Keywords:  angiogenesis; endothelial cells; glucose; hypoxia; metabolism

DOI:  https://doi.org/10.1161/ATVBAHA.124.320110
Sci Rep. 2025 Mar 17. 15(1): 9165

Integrated analysis of the expression profiles of the lncRNA-miRNA-mRNA ceRNA network in CASMCs under hypoxia and normoxia conditions in yak heart.

Shanshan Yang, Yan Cui, Sijiu Yu, Junfeng He, Rui Ma, Xuefeng Bai, Hui Zhang, Pengfei Zhao.

  Hypoxia causes the occurrence of right heart hypertrophy and right heart failure. However, the yak living in the hypoxic environment, does not exhibit hypoxia-related pathological features. Therefore, It is of great significance to explore the hypoxia adaptation mechanism of yak heart. In this study, the yak heart coronary vascular smooth muscle cells (CASMCs) were treated with 21% O2 (normoxic group) and 5% O2 (hypoxic group). The results showed that hypoxia could promote the proliferation of CASMCs. Subsequently, we sequenced CASMCs in normoxic and hypoxic groups. The analysis revealed differential expression of 835 mRNAs, 285 lncRNAs and 126 miRNAs were between the two groups. GO and KEGG analysis showed that the differentially expressed genes were predominantly associated with extracellular matrix components, transcription factor activity, protein binding, immune system processes, metabolic processes and cell development processes and TGF-β, MAPK, cAMP, mTOR, PI3K-Akt and other signaling pathways. By constructing a network of mRNAs, miRNAs and lncRNAs based on the major differentially expressed RNAs, core regulatory elements associated with hypoxic adaptive function were identified. Our study may help to prove the potential role of differential genes related to hypoxic adaptation, and enhanced understanding of the molecular mechanisms of hypoxic adaptation in yak heart.

Keywords:  CeRNA network; Coronary vascular smooth muscle cells; Hypoxic adaptation; LncRNA; MiRNA; Yak

DOI:  https://doi.org/10.1038/s41598-025-85483-4
Mol Med. 2025 Mar 20. 31(1): 107

Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia.

Prosperl Ivette Wowui, Richard Mprah, Marie Louise Ndzie Noah, Joseph Adu-Amankwaah, Anastasia Wemaaatu Lamawura Kanoseh, Li Tao, Diana Chulu, Simon Kumah Yalley, Saffia Shaheen, Hong Sun.

   BACKGROUND: The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. The insufficient oxygenation of the cellular space leads to hypoxia. Hypobaric hypoxia (HH) is the reduction in oxygen partial pressure and atmospheric pressure during ascent to high altitudes. This state induces a maladaptive response. Women and how hormones like estrogen influence hypoxia have not been explored with most research being conducted on males. In this study, we investigated the effects of estrogen and GPER on HIF-1a and MIF expression, cardiac arrhythmias, and inflammation during hypobaric hypoxia.
METHODS: Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. 2 weeks after the operation, the mice were treated with estrogen (40 mg/kg) as a therapeutic intervention and placed in a hypoxic chamber at an altitude of 6000 m for 7 days. Cardiac electrical activity was assessed using electrocardiography. Alterations in protein expression, inflammatory, and GPER pathways were investigated using western blotting, ELISA, and immunofluorescence. Histological assessment was performed using Masson's trichrome staining. Peritoneal macrophages were isolated for in vitro study.
RESULTS: Under hypobaric hypoxia (HH), the ovariectomized (OVX) group showed increased macrophage migration inhibitory factor (MIF) and hypoxia-inducible factor-1 alpha (HIF-1α) expression. In contrast, these factors were downregulated in the estrogen-treated and control groups. HH also caused cardiac inflammation and fibrosis, especially in the OVX + HH group, which had elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) and decreased anti-inflammatory cytokines (TGF-β, IL-10). Inhibition with G15 (a GPER antagonist) increased MIF and HIF-1α, whereas activation with G1 (a GPER agonist) decreased their expression, highlighting GPER's crucial role in regulating MIF during HH.
CONCLUSION: Estrogen regulates HIF-1α and MIF expression through the GPER during hypobaric hypoxia, suggesting a potential therapeutic pathway to mitigate maladaptive responses during high-altitude ascent.

Keywords:  Estrogen; G-protein-coupled estrogen receptor; Hypobaric hypoxia; Hypoxia-inducible factor-1α; Macrophage migration inhibitory factor; Myocardial inflammation

DOI:  https://doi.org/10.1186/s10020-025-01144-2
Comp Biochem Physiol A Mol Integr Physiol. 2025 Mar 19. pii: S1095-6433(25)00044-3. [Epub ahead of print] 111846

Knockdown of cytochrome P450 1 A (cyp1a) gene suppresses growth and oxygen tolerance in zebrafish.

Min Li, Dongjie Wang, Xiaoping Huang, Shulan Wang, Zhenhan Chen, Muhammad Junaid, Shaolin Xie.

  Cyp1a (cytochrome P450 1 A) is critical for metabolizing endogenous substances and environmental chemicals. In this study, a zebrafish strain KI (cyp1a:mcherry), exhibiting low cyp1a gene expression, was compared with wild-type zebrafish (WT) to investigate the effects of cyp1a on growth and hypoxia tolerance. The results demonstrated that low cyp1a expression significantly inhibited zebrafish growth and reduced hypoxia tolerance. Specifically, KI zebrafish exhibited slower growth rates and higher sensitivity to low oxygen conditions compared to WT. These physiological phenotypes directly link low cyp1a expression to impaired growth and reduced environmental adaptation. Transcriptomic analysis revealed potential mechanisms underlying these effects, including up-regulation of digestive system-related genes (e.g., cpa1, cpb1) and dysregulation of pathways involved in detoxification, stress response, and steroid biosynthesis. These findings highlight the importance of maintaining normal cyp1a expression for healthy growth and environmental adaptation in zebrafish.

Keywords:  Cyp1a gene; Growth; Oxygen tolerance; Transcriptome analysis; Zebrafish

DOI:  https://doi.org/10.1016/j.cbpa.2025.111846
Mol Med. 2025 Mar 14. 31(1): 100

Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α.

Yafen Chen, Shuyao Shan, Qiqi Xue, Yan Ren, Qihong Wu, Jiawei Chen, Ke Yang, Jiumei Cao.

   BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hypoxic conditions.
METHODS: An AMI animal model was established via ligation of the left anterior descending (LAD) coronary artery. Gene expression in the infarcted region was evaluated at various time points. Sirt1 overexpression and control lentivirus were administered to the peri-infarct region of mice heart. After LAD ligation, assessment on myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were performed. In vitro, primary mouse cardiomyocytes subjected to hypoxia were analyzed for gene expression, while interactions among Sirt1, Phd3, and Hif-1α were explored using diverse treatment approaches.
RESULTS: A significant reduction in Sirt1 and Phd3 expression, along with an increase in Hif-1α and cleaved caspase-3, was observed in a time-dependent manner post-myocardial infarction (MI). In vitro findings revealed that hypoxia decreased nuclear Sirt1 and cytoplasmic Phd3 levels while promoting a time-dependent increase in Hif-1α and cleaved caspase-3. Furthermore, Sirt1 overexpression enhanced Phd3 expression in cardiomyocytes, suppressed Hif-1α and cleaved caspase-3 levels, and alleviated hypoxia-induced cardiomyocyte apoptosis. Notably, knockdown of Phd3 negated Sirt1's inhibitory effect on Hif-1α, whereas Hif-1α knockdown promoted Sirt1 expression. Sirt1 overexpression reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function.
CONCLUSIONS: Sirt1 effectively reduces cardiomyocyte apoptosis and myocardial infarction size while enhancing cardiac function post-MI, primarily through the Phd3/Hif-1α signaling pathway.

Keywords:  Acute myocardial infarction; Apoptosis; Hif-1α; Hypoxia; Phd3; Sirt1

DOI:  https://doi.org/10.1186/s10020-025-01155-z
Acta Physiol (Oxf). 2025 Apr;241(4): e70030

Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels-Lessons from rat, pig, mouse, and human.

Christian Staehr, Victoria Hinkley, Vladimir V Matchkov, Rajkumar Rajanathan, Line Mathilde B Hansen, Yvonne Eiby, Nathan Luque, Ian Wright, Stella T Bjorkman, Stephanie M Miller, Rohan S Grimley, Andrew Dettrick, Kirat Chand, Hong L Nguyen, Nicole M Jones, Tim V Murphy, Shaun L Sandow.

   AIM: In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BKCa) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BKCa in cerebral arteries was examined.
METHODS: Immunohistochemistry analyzed BKCa expression in EC and smooth muscle (SM) of the middle-cerebral artery (MCA) from rat, piglet, and mouse, and pial arteriole of human. Pressure myography with pharmacological intervention characterized EC-BKCa and TRPV4 function in rat MCA. Electron microscopy determined caveolae density and vessel properties in rat and mouse MCA.
RESULTS: In rat, pig, and human cerebral vessels, EC-BKCa was absent in normoxia; present after chronic (rat) and acute hypoxia (pig), post-ischemic stroke in human vessels, and after endothelin-1-induced stroke in rats. Mouse MCA EC-BKCa expression increased after acute hypoxia. In rat MCA post-hypoxia and stroke, EC and SMC caveolae density increased, with reduced medial thickness, and unchanged diameter. Caveolae and BKCa did not colocalize. In rat MCA, iberiotoxin (IbTx) potentiated pressure-induced tone in hypoxia/stroke, but not in normoxia. In normoxia, overall MCA tone was unaffected by endothelial removal, but was increased in hypoxia/stroke, where there was no additive effect of endothelial removal and IbTx on tone. Functional TRPV4 was expressed in EC of rat MCA post-stroke.
CONCLUSIONS: In post-hypoxia/stroke, but not in normoxia, EC-BKCa contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BKCa is a potential therapeutic target to control blood flow post-hypoxia/stroke.

Keywords:  BKCa; blood flow; endothelium; hypoxia; ion channel; stroke

DOI:  https://doi.org/10.1111/apha.70030
Front Cell Infect Microbiol. 2025 ;15 1522431

Optimized oxygen therapy improves sleep deprivation-induced cardiac dysfunction through gut microbiota.

Shuqi Cai, Zixuan Li, Jie Bai, Yue Ding, Ruisang Liu, Liben Fang, Dengyong Hou, Sheng Zhang, Xiaohui Wang, Yujia Wang, Yuyu Jiang, Yan Xiang, Wenhui Wu, Ying He, Yunkai Zhang, Xiaomeng Ren.

  Adequate sleep is of paramount importance for relieving stress and restoring mental vigor. However, the adverse physiological and pathological responses resulting from sleep insufficiency or sleep deprivation (SD) are becoming increasingly prevalent. Currently, the impact of sleep deficiency on gut microbiota and microbiota-associated human diseases, especially cardiac diseases, remains controversial. Here, we employed the following methods: constructed an experimental sleep-deprivation model in mice; conducted 16S rRNA sequencing to investigate the changes in gut microbiota; through fecal microbiota transplantation (FMT) experiments, transplanted fecal microbiota from sleep-deprived mice to other mice; established an environment with a 30% oxygen concentration to explore the therapeutic effects of oxygen therapy on gut microbiota-associated cardiac fibrosis and dysfunction; and utilized transcriptome data to study the underlying mechanisms of oxygen therapy. The results revealed that: sleep-deprived mice exhibited weakness, depression-like behaviors, and dysfunction in multiple organs. Pathogenic cardiac hypertrophy and fibrosis occurred in sleep-deprived mice, accompanied by poor ejection fraction and fractional shortening. 16S rRNA sequencing indicated that sleep deprivation induced pathogenic effects on gut microbiota, and similar phenomena were also observed in mice that received fecal microbiota from sleep-deprived mice in the FMT experiments. The environment with a 30% oxygen concentration effectively alleviated the pathological impacts on cardiac function. Transcriptome data showed that oxygen therapy targeted several hypoxia-dependent pathways and inhibited the production of cardiac collagen. In conclusion, these results demonstrate the significance of sufficient sleep for gut microbiota and may represent a potential therapeutic strategy, where the oxygen environment exerts a protective effect on insomniacs through gut microbiota.

Keywords:  cardiac dysfunction; gut microbiota; hypoxia; oxygen therapy; sleep deprivation

DOI:  https://doi.org/10.3389/fcimb.2025.1522431
Nat Commun. 2025 Mar 18. 16(1): 2684

A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation.

Li Li, Heinz Hammerlindl, Susan Q Shen, Feng Bao, Sabrina Hammerlindl, Steven J Altschuler, Lani F Wu.

Severe acute hypoxic stress is a major contributor to the pathology of human diseases, including ischemic disorders. Current treatments focus on managing consequences of hypoxia, with few addressing cellular adaptation to low-oxygen environments. Here, we investigate whether accelerating hypoxia adaptation could provide a strategy to alleviate acute hypoxic stress. We develop a high-content phenotypic screening platform to identify compounds that fast-track adaptation to hypoxic stress. Our platform captures a high-dimensional phenotypic hypoxia response trajectory consisting of normoxic, acutely stressed, and chronically adapted cell states. Leveraging this trajectory, we identify compounds that phenotypically shift cells from the acutely stressed state towards the adapted state, revealing mTOR/PI3K or BET inhibition as strategies to induce this phenotypic shift. Importantly, our compound hits promote the survival of liver cells exposed to ischemia-like stress, and rescue cardiomyocytes from hypoxic stress. Our "phenopushing" platform offers a general, target-agnostic approach to identify compounds and targets that accelerate cellular adaptation, applicable across various stress conditions.

DOI: https://doi.org/10.1038/s41467-025-57754-1