bims-oxygme 2025-06-15 papers

Issue of 2025–06–15
ten papers selected by
Onurkan Karabulut, Berkeley City College

J Biol Chem. 2025 Jun 06. pii: S0021-9258(25)02194-5. [Epub ahead of print] 110344

The Stage-Specific Roles of HIF-1α in Regulating mESCs Pluripotency During Oxygen Transition.

Meng Li, Yang Cao, Huaizhang Jin, Ao Wang, Jian Ruan, Shan Lu, Guosheng Lv, Guoping Zhu, Yang Lei, Xiaopeng Shen.

Hypoxia-inducible factor 1-alpha (HIF-1α) is a key transcription factor in cellular responses to oxygen levels. This study investigated HIF-1α's binding dynamics to the genome during the transition from normoxia to hypoxia in mouse embryonic stem cells (mESCs). Analyzing HIF-1α ChIP-seq data under normoxia, acute hypoxia, and stable hypoxia revealed a "bind-release-bind" pattern, with the weakest binding during acute hypoxia and the strongest during stable hypoxia. Gene ontology (GO) and KEGG analyses identified distinct gene sets and pathways regulated by HIF-1α in these conditions, with significant effects on pluripotency under normoxia and stable hypoxia. HIF-1α also partnered with different transcription factors depending on the oxygen level, further influencing its functions. RNA-seq data and knockdown experiments confirmed HIF-1α's essential role in maintaining mESCs pluripotency under normoxia and stable hypoxia, with minimal impact under acute hypoxia. These findings enhance our understanding of HIF-1α's regulatory mechanisms and its role in cellular hypoxic responses.

Keywords: HIF-1α; dynamic regulation; embryonic stem cells; normoxia-hypoxia transition; pluripotency

DOI: https://doi.org/10.1016/j.jbc.2025.110344

Arch Biochem Biophys. 2025 Jun 07. pii: S0003-9861(25)00207-3. [Epub ahead of print] 110494

Effect of Metformin on Spontaneous Calcium Signaling in Cultured Astrocytes during Normoxic and Hypoxic Conditions.

Natasa Svirskiene, Gytis Svirskis, Silvija Jankeviciute, Vilmante Borutaite.

Astrocyte function is controlled by intracellular Ca2+ signaling. On the other hand, hypoxia influences calcium dynamics and its homeostatic range because of reduction of ATP synthesis, which inhibits ATP dependent processes. By using Ca2+ sensitive fluorescence dye, we studied how metformin changed spontaneous oscillating Ca2+ signals in soma of astrocytes in monocultures, prepared from rat brains. Mild hypoxic conditions (2% O2) applied for 24 h had no effect on astrocyte viability; however, it reduced the relative amplitude of Ca2+ signals, slowed the decay of the signals, and increased the period of spontaneous oscillations. Lower concentrations of metformin, 250 μM or 500 μM, applied before hypoxia reduced this influence by partially restoring the amplitude, fastening the decay, and reducing the period of Ca2+ signaling. In contrast, higher concentration, 1mM of metformin exaggerated the effects of hypoxia by reducing signals, slowing their decay and prolonged the period between signals. Unexpectedly, in astrocytes grown under normoxic conditions, all concentrations of metformin after one hour of application had effects similar to hypoxia for Ca2+ signaling. In conclusion, our data show that mild hypoxia reduces Ca2+signaling in astrocyte cell monocultures, and low concentrations of metformin under mild hypoxic conditions help to rescue the functioning of astrocytes by conditioning the cells to prolonged hypoxic influence.

Keywords: Astrocytes; Brain ischemia; Ca(2+) signaling; Hypoxia; Metformin

DOI: https://doi.org/10.1016/j.abb.2025.110494

Ann Med Surg (Lond). 2025 Jun;87(6): 3635-3659

Oxygen deprivation in breast cancer: mechanisms, pathways, and implications.

Emmanuel Ifeanyi Obeagu.

Hypoxia, a state of reduced oxygen availability, is a defining feature of the tumor microenvironment in breast cancer. It arises from the rapid proliferation of cancer cells, which outpaces the development of adequate vasculature. This oxygen deprivation triggers a cascade of molecular and cellular adaptations that enable tumor cells to survive and thrive under hostile conditions. Key among these is the stabilization of hypoxia-inducible factors, which regulate genes involved in angiogenesis, metabolic reprogramming, immune evasion, and cell survival. Hypoxia significantly influences breast cancer behavior, promoting tumor aggressiveness, therapeutic resistance, and metastatic potential. The hypoxic microenvironment fosters angiogenesis through vascular endothelial growth factor signaling, albeit leading to abnormal and inefficient vasculature. It also reprograms cancer cell metabolism towards glycolysis, supporting survival and growth in oxygen-deprived regions. Furthermore, hypoxia modulates immune responses, suppressing anti-tumor immunity while promoting the recruitment of immunosuppressive cells. These multifaceted effects underscore hypoxia's pivotal role in shaping the clinical trajectory of breast cancer.

Keywords: breast cancer; hypoxia; hypoxia-inducible factors; therapeutic resistance; tumor microenvironment

DOI: https://doi.org/10.1097/MS9.0000000000003334

Discov Med. 2025 Jun;37(197): 1049-1061

Hypoxia-Induced Up-Regulation of ACSS2 Drives the PI3K/AKT/mTOR Pathway Through HMGCS1 to Enhance the Proliferation and Stemness of Pancreatic Cancer Cells.

Zhangcheng Zhao, Gengyu Li, Beibei Zhang, Yuansen Zhang.

OBJECTIVE: Pancreatic cancer (PC) is a type of highly malignant tumor associated with poor prognosis, whose progression is driven by hypoxia in the tumor microenvironment. This study aims to explore the effects of hypoxia-induced upregulation of acetyl-CoA synthetase 2 (ACSS2) on the proliferation and stemness of PC cells and its potential molecular mechanism, so as to provide new targets and therapy strategies for the PC.
MATERIALS AND METHODS: PC cells (PANC-1) were cultured under separate conditions: hypoxic and normoxic. Cell models of ACSS2 overexpression, ACSS2 knockdown and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) knockdown were constructed using transfection technique. Cell counting kit 8 (CCK-8) and clonal formation assay were used to assess cell viability, and cell stemness was analyzed by means of sphere-formation assay and detection of stem-related markers. A mouse tumor model was established by axilla injection of tumor cells, and tumor growth was evaluated by measuring the volume and weight of the isolated tumors. Relative mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry.
RESULTS: Hypoxic condition upregulated the expression of ACSS2 in PC cells. CCK-8 and clonal formation assays showed that upregulation of ACSS2 promoted cell proliferation (p < 0.001), while knockdown of ACSS2 inhibited cell proliferation (p < 0.001). Sphere formation assay and stemness marker detection showed that ACSS2 upregulation could maintain cell stemness (p < 0.001), while knockdown could inhibit it (p < 0.01). Through mechanistic studies, we found that ACSS2 activated phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway through HMGCS1. Interference with HMGCS1 inhibited pathway activation caused by ACSS2 upregulation and hindered cell proliferation and stemness. In vivo experiments further demonstrated that ACSS2 accelerated PC xenograft tumor growth and promoted tumor stemness.
CONCLUSION: Hypoxia induces upregulation of ACSS2 and activates PI3K/AKT/mTOR pathway through HMGCS1, thereby enhancing the proliferation and stemness of PC cells. This finding offers a novel perspective for understanding the development mechanism of PC and highlights a potential molecular target for developing targeted therapeutic strategies.

Keywords: ACSS2; HMGCS1; PI3K/AKT/mTOR; pancreatic cancer

DOI: https://doi.org/10.24976/Discov.Med.202537197.93

Hum Reprod Open. 2025 ;2025(3): hoaf027

Hypoxia exposure impairs male fertility via inhibiting Septin2-mediated spermatogonial proliferation.

Zhibin Li, Shuying Li, Yufeng Xiao, Junfeng Guo, Jianchun Zhou, Yang Chen, Juan Yang, Chunli Gong, Bing He, Yuyun Wu, Nannan Gao, Huan Yang, Limin Gao, Hua Hu, Yunfang Zhang, Shiming Yang.

STUDY QUESTION: What are the molecular mechanisms underlying hypoxia-induced male reproductive impairment?
SUMMARY ANSWER: Hypoxia compromises Septin2 (Sept2) transcription in spermatogonia, which impedes spermatogonial proliferation through protein phosphatase 2A (PP2A)-dependent AKT dephosphorylation.
WHAT IS KNOWN ALREADY: Hypoxia is associated with impaired spermatogenesis and poor sperm parameters in men. Spermatogonia proliferation, a crucial early step in spermatogenesis, is essential for maintaining the spermatogenic cell population and ensuring sperm quality. However, the connection between hypoxia and spermatogonial proliferation remains poorly understood, and treatment options for hypoxia-related reproductive disorders are limited.
STUDY DESIGN SIZE DURATION: A cross-sectional study analyzed semen samples from 24 high-altitude (HA) residents, 6 pathological hypoxia (PH) patients, and 19 healthy controls to evaluate hypoxia-associated sperm parameter alterations. Complementary animal studies employing a hypobaric chamber-induced hypoxic mouse model (n = 5) confirmed reproductive impairments through assessment of birth rates, sperm quality, and testicular histopathology. Transcriptomic profiling of hypoxic versus normoxic mouse testes (n = 3/group) identified spermatogonial proliferation defects as a predominant pathological feature and pinpointed Sept2 as a candidate mediator. Subsequent mechanistic investigations employed in vitro hypoxic culture of spermatogonial cell lines under hypoxic conditions coupled with pharmacological modulation of PP2A activity in mice (n = 3-5 per intervention group) to delineate the underlying molecular pathways.
PARTICIPANTS/MATERIALS SETTING METHODS: Semen parameters were evaluated using computer-assisted sperm analysis (CASA; for sperm concentration, count, and motility), morphological staining (Pap staining for sperm deformity), and eosin-nigrosin staining (for sperm viability). In the hypoxic mouse model, fertility outcomes were assessed through fertility assessment (mating experiments), sperm parameters (CASA), testicular histology (H&E staining), and spermatogonia proliferation (immunohistochemistry and qPCR). In hypoxic spermatogonial cell models, cell proliferation was detected using CCK-8, EdU incorporation, flow cytometry, and western blotting. Sept2 manipulation (knockdown/overexpression), followed by mechanistic analyses (dual-luciferase reporter assay, DNA pulldown/mass spectrometry, TMT-based quantitative proteomics, co-immunoprecipitation, etc.), was performed to investigate the mechanism underlying hypoxia-regulated spermatogonia proliferation. The SEPT2 inhibitor forchlorfenuron (FCF), the PP2A agonists celastrol, erlotinib, and FTY720, as well as PP2A inhibitor okadaic acid (OA) were used to investigate the role of the SEPT2-PP2A-AKT axis in male fertility regulation.
MAIN RESULTS AND THE ROLE OF CHANCE: Both human populations (HA residents and PH patients) and mouse model consistently demonstrated hypoxia-related reproductive dysfunction. Mechanistic analyses revealed that hypoxia significantly downregulated Sept2 expression in spermatogonia, concomitant with impaired proliferative capacity. Sept2 knockdown in normoxic mice phenocopied the hypoxia-induced defects in spermatogenesis. Complementary in vitro studies confirmed that Sept2 depletion impaired spermatogonial proliferation by inducing G1-S phase arrest, while its overexpression mitigated hypoxia-related proliferative defects. Further investigation revealed that hypoxia disrupts Sept2 transcription by interfering with the binding of RNA polymerase II subunit A (POLR2A) to the Sept2 promoter. The consequent reduction in Sept2 expression led to stabilization of the B56γ regulatory subunit of PP2A, resulting in enhanced AKT dephosphorylation and subsequent suppressed spermatogonial proliferation. Pharmacological intervention with the PP2A inhibitor OA restored reproductive competence and sperm quality in hypoxic mice, whereas PP2A agonists exacerbated these deficits.
LARGE SCALE DATA: RNA-seq data are deposited in China National Center for Bioinformation (CNCB) under accession number PRJCA035733.
LIMITATIONS REASONS FOR CAUTION: This study focused on the effects of hypoxia on sperm parameters. Additional factors such as alterations in reproductive hormones and sexual function may contribute to hypoxia-induced infertility and warrant further research.
WIDER IMPLICATIONS OF THE FINDINGS: This study identifies the SEPT2-PP2A/B56γ-AKT axis as a key regulator in hypoxia-related spermatogonia proliferation impairment. PP2A inhibitors such as OA may offer a therapeutic strategy to protect male fertility under hypoxic conditions.
STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (No. 82101688) and Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-MSX0943). The authors have no conflicts of interest to declare.

Keywords: PP2A /AKT; Septin2; hypoxia; proliferation; spermatogonia

DOI: https://doi.org/10.1093/hropen/hoaf027

Int J Mol Sci. 2025 May 26. pii: 5101. [Epub ahead of print]26(11):

HIF-1α-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion.

Michael Springer, Zeynep Aydin Burakgazi, Anastasiia Domukhovska, Ben Nafchi, Michael C Beary, Arielle Acquisto, Juliette Acquisto, Vladyslav Komarov, Madison Jensen, Brandon Gulledge, Maksym Poplavskyi, Md Gias Uddin, Gamal Rayan, Shoshanna N Zucker.

Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions-including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes.

Keywords: adherens junctions; angiogenesis; desmosomes; gap junctions; hypoxia; matrix metalloproteinases; metastasis; tight junctions; tumor microenvironment

DOI: https://doi.org/10.3390/ijms26115101

bioRxiv. 2025 Jun 08. pii: 2025.06.04.657917. [Epub ahead of print]

Comparative transcriptomics of iPSC-derived cardiomyocytes in a high and a low altitude population.

O A Gray, D B Witonsky, A Di Rienzo.

Tibetan adaptation to high-altitude hypoxia remains a classic example of Darwinian selection in humans. To identify adaptive traits that might have evolved in Tibetans in response to long-term exposure to hypoxia, we previously established a library of induced pluripotent stem cells (iPSCs), derived from Tibetan and Han Chinese individuals, as a robust model system for the exploration of condition-specific molecular and cellular responses. We used this system to characterize and compare the transcriptome of iPSC-derived endothelial cells and found that angiogenesis, energy metabolism and immune pathways differ between the cell lines from these two populations. Here, we harness the same experimental system to characterize and compare the transcriptome of iPSC-derived cardiomyocytes in Tibetan and Han Chinese in hypoxia. We find that several pathways, such as the hypoxia, myogenesis and glycolysis pathways, are significantly enriched for differentially expressed genes across populations. These pathways are candidate targets of natural selection due to exposure to the high-altitude hypoxic environment and point to adaptive cardiac traits such as sustained cardiac function in hypoxia. A better understanding of these adaptations may offer insights into novel therapeutic strategies for hypoxia-related cardiovascular conditions, such as pulmonary hypertension and ischemic heart disease.

DOI: https://doi.org/10.1101/2025.06.04.657917

Cancers (Basel). 2025 May 23. pii: 1756. [Epub ahead of print]17(11):

TSGA10 as a Model of a Thermal Metabolic Regulator: Implications for Cancer Biology.

Ali Amini, Farzad Taghizadeh-Hesary, John Bracht, Babak Behnam.

TSGA10, a multifunctional protein critical for mitochondrial coupling and metabolic regulation, plays a paradoxical role in cancer progression and carcinogenesis. Here, we outline a potential mechanism by which TSGA10 mediates metabolism in oncogenesis and thermal modulation. Initially identified in spermatogenesis, TSGA10 interacts with mitochondrial Complex III: it directly binds cytochrome c1 (CytC1). In our model, TSGA10 optimizes electron transport to minimize reactive oxygen species (ROS) and heat production while enhancing Adenosine Triphosphate (ATP) synthesis. In cancer, TSGA10's expression is context-dependent: Its downregulation in tumors like glioblastoma might disrupt mitochondrial coupling, promoting electron leakage, ROS accumulation, and genomic instability. This dysfunction would be predicted to contribute to a glycolytic shift, facilitating tumor survival under hypoxia. Conversely, TSGA10 overexpression in certain cancers suppresses HIF-1α, inhibiting glycolysis and metastasis. TSGA10 and HIF-1α engage in mutual counter-regulation-TSGA10 represses HIF-1α to sustain oxidative phosphorylation (OXPHOS), while HIF-1α suppression of TSGA10 under hypoxia or thermal stress amplifies glycolytic dependency. This interplay is pivotal in tumors adapting to microenvironmental stressors, such as cold-induced mitochondrial uncoupling, which mimics brown adipose tissue thermogenesis to reduce ROS and sustain proliferation. Tissue-specific TSGA10 expression further modulates cancer susceptibility: high levels in the testes and brain may protect against thermal and oxidative damage, whereas low expression in the liver permits HIF-1α-driven metabolic plasticity. Altogether, our model suggests that TSGA10 plays a central role in mitochondrial fidelity. We suggest that its crosstalk with oncogenic pathways position it as a metabolic rheostat, whose dysregulation fosters tumorigenesis through ROS-mediated mutagenesis, metabolic reprogramming, and microenvironmental remodeling. Targeting the hypothesized TSGA10-mediated mitochondrial coupling may offer therapeutic potential to disrupt cancer's adaptive energetics and restore metabolic homeostasis.

Keywords: Complex III (CytC1); HIF-1α; TSGA10; Warburg effect; carcinogenesis; mitochondrial coupling

DOI: https://doi.org/10.3390/cancers17111756

Chem Biol Interact. 2025 Jun 09. pii: S0009-2797(25)00225-X. [Epub ahead of print] 111595

Characterization of a gene expression biomarker predictive of hypoxia-inducible factor-1 modulation.

J Christopher Corton, Brian Chorley, Jie Liu.

We describe here a gene expression biomarker that can accurately identify chemicals and genetic conditions that perturb hypoxia-inducible factor-1 (HIF-1), a transcription factor critical for the cellular response to hypoxia involved in the pathophysiology of cancer, inflammation, and ischemia. The HIF-1 biomarker genes were identified from transcript profiles in a variety of human cell lines after hypoxia as well as genetic knockdown of the HIF1A gene. The HIF-1 biomarker of 122 genes was found to be enriched for: genes bound by HIF-1 using ChIP-Seq, metabolic pathways regulated by HIF-1 (e.g., gluconeogenesis). Using Ingenuity Pathway Analysis, HIF-1 was the top predicted regulator of the genes. The biomarker could identify activation of HIF-1 by overexpression of the HIF1A gene or suppression of the negative regulator, von-Hipple Lindau (VHL) gene; suppression of HIF-1 occurred by inhibition of the expression of HIF1A or the heterodimer partner aryl hydrocarbon receptor nuclear translocator (ARNT). The biomarker was specific for HIF-1 activation, as activation or suppression of the HIF-2 gene was not detected by the biomarker. Using a reference chemical set with 180 positives and 45 negatives, the balanced accuracy of the HIF-1 biomarker to identify activation was 94.1%. An in-silico screen of a gene expression compendium identified hundreds of potential activators. Eleven of these were selected for verification and all were found to activate HIF-1 biomarker genes in wild-type but not HIF1A-null cells. The HIF-1 biomarker will be a useful tool to identify environmentally relevant chemicals that affect HIF-1 in high-throughput transcriptomics screening studies.

Keywords: ChIP-Seq; gene expression biomarker; human gene expression compendium; hypoxia; hypoxia-inducible factor-1

DOI: https://doi.org/10.1016/j.cbi.2025.111595

J Cardiovasc Transl Res. 2025 Jun 11.

Hypoxia/reoxygenation-induced Glycolysis Mediates Myocardial Ischemia-reperfusion Injury Through Promoting the Lactylation of GPX4.

Yihua Wang, Qiang Yue, Xiurong Song, Wei Du, Rui Liu.

Myocardial ischemia-reperfusion injury (MIRI) is an injury mechanism of myocardial infarction, related to ferroptosis and glycolysis. Lactate produced by glycolysis promotes protein lactylation. This study aimed to investigate the correlation between glycolysis, ferroptosis, and GPX4 lactylation in MIRI. Hypoxia/reoxygenation (H/R) increased glucose uptake, lactate production, ECAR, OCR, LDH release, lipid ROS, Fe2+, GSH, MDA contents, and cell apoptosis, and decreased GSH level in the H9C2 cells, suggesting H/R promoted glycolysis and ferroptosis. 2-DG treatment relieved the H/R-induced injury, while lactate treatment aggravated it. Besides, 2-DG suppressed lactylation of GPX4 at K218 and K228 sites and increased its protein stability. GPX4 overexpression relieved the injury caused by H/R, and alleviated cardiac injury, decreased cardiomyocyte ferroptosis in heart tissues of MIRI rats. In conclusion, GPX4 lactylation facilitated H/R-induced cardiomyocyte injury and aggravated MIRI in rats. Our findings provided new insight into targeting glycolysis and GPX4 lactylation as therapeutic strategies of MIRI.

Keywords: GPX4; Glycolysis; H/R; Lactylation; MIRI

DOI: https://doi.org/10.1007/s12265-025-10628-9