bims-oxygme 2025-10-19 papers

Issue of 2025–10–19
five papers selected by
Onurkan Karabulut, Berkeley City College

Cell Death Dis. 2025 Oct 16. 16(1): 732

HypoxamiRs: the hidden architects of tissue adaptation in hypoxia.

Hypoxia, or reduced oxygen availability, triggers a spectrum of adaptive responses across tissues, including angiogenesis, metabolic reprogramming, and modulation of survival pathways. Central to these adaptations are hypoxia-regulated microRNAs (miRNAs), hypoxamiRs, which fine-tune gene expression in a context-dependent manner. HypoxamiRs are transcriptionally regulated by hypoxia-inducible factors (HIFs), tissue-specific transcriptional programs, and microenvironmental cues, enabling precise responses to hypoxia. HypoxamiRs exhibit distinct expression profiles across tissues, reflecting their specialized roles. In ischemic tissue, they activate angiogenic and cytoprotective programs, while in metabolically active or malignant tissues, they rewire energy production and promote survival. This tissue specificity underlies their dual function as both regulators of physiological adaptation and drivers of pathology in chronic hypoxia. Increasingly, hypoxamiRs are being recognized as non-invasive biomarkers and therapeutic targets in diseases such as cancer, cardiovascular disorders, and fibrosis. Compared to canonical hypoxia pathways, hypoxamiRs offer a versatile and finely tunable layer of regulation. This review presents a unified framework in which hypoxamiRs emerge not merely as downstream effectors of HIF signaling but as integrative architects at the intersection of oxygen sensing, epigenetic remodeling, and cellular identity. Their coordinated regulatory functions make them promising tools for precision medicine in hypoxia-related diseases. Understanding how hypoxamiRs operate across tissues and pathologies may unlock new diagnostic and therapeutic strategies for complex, oxygen-sensitive conditions.

DOI: https://doi.org/10.1038/s41419-025-08091-0

Pathol Res Pract. 2025 Oct 15. pii: S0344-0338(25)00464-9. [Epub ahead of print]276 156271

Hypoxia-driven metabolic and molecular reprogramming: From tumor microenvironment to therapeutic interventions.

Diksha Devi, Kanchan Sharma, Tabish Khan, Hema Rani, Rekha Rana, Heena Sharma, Parjinder Kaur, Lokesh Prajapati, Adil Rizwan, Moses Allieu, Sampita Pal, Vishal Kumar, Sunny Kumar.

Hypoxia, characterized by reduced oxygen availability, significantly contributes to cancer development by affecting tumor growth and spread. In fast-growing tumors, the scarcity of oxygen forces cancer cells to modify their molecular structure and metabolism to survive and multiply. These alterations are predominantly governed by hypoxia-inducible factors (HIFs), with HIF-1α and HIF-2α serving crucial roles in the activation of genes related to invasion, angiogenesis, metabolic reprogramming, and metastasis. Such changes promote tumor development in low-oxygen environments and enhance resistance to conventional therapies. Hypoxia influences various aspects of cancer progression, heightening the risk of malignancy and worsening prognosis. This study investigates the fundamental mechanisms by which hypoxia influences tumor biology, including the facilitation of the epithelial-to-mesenchymal transition (EMT), the enhancement of angiogenesis through vascular endothelial growth factor (VEGF), and the metabolic shift from oxidative phosphorylation to glycolysis. In this review, we aim to elucidate the complex interaction of metabolic and molecular mechanisms within the cancer microenvironment under hypoxic conditions, which not only fosters tumor growth but also contributes to therapeutic resistance, making hypoxia a critical factor in cancer treatment strategies.

Keywords: And Metabolic alterations; Cancer; Hypoxia; Tumor-microenvironment (TME)

DOI: https://doi.org/10.1016/j.prp.2025.156271

Int J Mol Sci. 2025 Sep 23. pii: 9272. [Epub ahead of print]26(19):

Hypoxia and Tissue Regeneration: Adaptive Mechanisms and Therapeutic Opportunities.

Isabel Cristina Vásquez Vélez, Carlos Mario Charris Domínguez, María José Fernández Sánchez, Zayra Viviana Garavito-Aguilar.

Reduced oxygen availability, or hypoxia, is an environmental stress factor that modulates cellular and systemic functions. It plays a significant role in both physiological and pathological conditions, including tissue regeneration, where it influences angiogenesis, metabolic adaptation, inflammation, and stem cell activity. Hypoxia-inducible factors (HIFs) orchestrate these responses by activating genes that promote survival and repair, although HIF-independent mechanisms, particularly those related to mitochondrial function, are also involved. Depending on its duration and severity, hypoxia may exert either beneficial or harmful effects, ranging from enhanced regeneration to fibrosis or maladaptive remodeling. This review explores the systemic and cellular effects of acute, chronic, intermittent, and preconditioning hypoxia in the context of tissue regeneration. Hypoxia-driven responses are examined across tissues, organs, and complex structures, including the heart, muscle, bone, vascular structures, nervous tissue, and appendages such as tails. We analyze findings from animal models and in vitro studies, followed by biomedical and pharmacological strategies designed to modulate hypoxia and their initial exploration in clinical settings. These strategies involve regulatory molecules, signaling pathways, and microRNA activity, which are investigated across species with diverse regenerative capacities to identify mechanisms that may be conserved or divergent among taxa. Lastly, we emphasize the need to standardize hypoxic conditions to improve reproducibility and highlight their therapeutic potential when precisely controlled.

Keywords: HIF signaling; cellular adaptation; comparative models; hypoxia; oxygen homeostasis; tissue regeneration

DOI: https://doi.org/10.3390/ijms26199272

J Physiol. 2025 Oct 14.

Hypoxia and the cytoskeleton.

Darragh Flood, Cormac T Taylor.

A highly-regulated and dynamic cytoskeleton is vital for functional cellular physiology and the maintenance of homeostasis. Although much is known about the mechanisms by which the cytoskeleton is regulated under physiological conditions, the effect of pathological stimuli and how this contributes to disease progression remains poorly understood. Hypoxia is a prominent microenvironmental feature of a range of pathological states including inflammation, cancer and ischaemia. In this review, we summarise what is known about the effects of hypoxia on the cytoskeleton and discuss the implications of this for physiology and disease.

Keywords: actin; cell physiology; cytoskeleton; hypoxia; hypoxia‐inducible factor; intermediate filaments; microtubules; molecular physiology

DOI: https://doi.org/10.1113/JP289565

Front Bioeng Biotechnol. 2025 ;13 1671013

A hypoxia-on-a-chip platform for modeling ischemic arrhythmogenesis and evaluating the effects of levosimendan and OR-1896 on ischemic human iPSC-derived cardiomyocytes.

Mahmoud Gaballah, Kaisla Walls, Fatma Zakzook, Joose Kreutzer, Jouko Levijoki, Katriina Aalto-Setälä.

Acute hypoxia is a major contributor to cardiomyocyte damage and dysfunction in ischemic heart disease, and the effective therapeutic strategies remain limited. Levosimendan, a calcium sensitizer with both inotropic and vasodilatory effects, along with its active metabolite OR-1896, is utilized in the treatment of acute heart failure. In this study, we investigated the cardioprotective and antiarrhythmic effects of levosimendan and its metabolite OR-1896 under hypoxic conditions using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). hiPSC-CMs were exposed to acute hypoxia and treated with levosimendan or its metabolite OR-1896. Structural integrity was assessed via immunostaining and electron microscopy imaging. Calcium transient abnormalities were evaluated using live-cell imaging. Hypoxia-induced injury was further assessed by measuring cardiac biomarkers and gene expression profiling of hypoxia-associated pathways. Hypoxia induced significant structural damage, including sarcomere disorganization, mitochondrial cristae fragmentation, and nuclear shrinkage, accompanied by increased release of cardiac biomarkers. Hypoxia also upregulated genes associated with the hypoxia response, oxidative stress, and apoptosis, while disrupting calcium handling and increasing arrhythmic events. Treatment with levosimendan and its metabolite OR-1896 preserved cellular structure, reduced biomarker release, and stabilized calcium transients, significantly reducing hypoxia-induced arrhythmogenesis. Both compounds also modulated gene expression, downregulating hypoxia-responsive and oxidative stress markers, and inhibiting apoptotic pathways. Notably, the metabolite OR-1896 exhibited protective effects comparable to or even greater than those of levosimendan. This study provides the first comprehensive evidence of the cardioprotective and antiarrhythmic properties of levosimendan's metabolite, demonstrating its ability to reduce hypoxia-induced cellular injury and correct abnormal Ca2+ transients. These findings highlight the therapeutic potential of levosimendan and its clinically significant long-acting metabolite, OR-1896, in the treatment of cardiac ischemia.

Keywords: calcium cycling; calcium cycling by antiarrhythmic effect; cardioprotection; human-induced pluripotent stem cell-derived cardiomyocytes; hypoxia; hypoxia by Ischemia modeling; levosimendan; levosimendan metabolite OR-1896

DOI: https://doi.org/10.3389/fbioe.2025.1671013