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Abstract
Hypoxia is a state of oxygen deficiency in tissues that triggers complex adaptive mechanisms to maintain cellular homeostasis. Hypoxia-inducible factors (HIF-1α and HIF-2α) play a central role in this process, regulating metabolic reprogramming, angiogenesis, erythropoiesis, and protection against oxidative stress. In this comprehensive review, we provide an in-depth analysis of the molecular pathways of oxygen sensing, including prolyl hydroxylases (PHD) and the HIF inhibitor factor (FIH), as well as HIF-independent mechanisms such as the role of succinate, hypoxamiRs (hypoxia-associated microRNAs), and epigenetic changes. We discuss tissue-specific adaptations in the heart, brain, liver, and skeletal muscles, the differences between acute, chronic, and intermittent hypoxia, as well as maladaptive effects leading to fibrosis and inflammation. Special attention is given to therapeutic prospects: from hypoxic preconditioning to HIF inhibitors/stabilizers and miRNA-based therapy. To increase reader engagement, the review includes interesting facts from the latest studies (2024–2026), such as the role of HIF in tissue regeneration and the prevention of hypoxic stress. The review is made as up-to-date and engaging as possible for readers ranging from students to specialists in medicine and biology.
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