Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. In mammals, HIFs are heterodimers consisting of an oxygen-sensitive α subunit and a stable β subunit. Three HIFα isoforms exist: HIF1α, HIF2α (also known as EPAS1), and HIF3α (IPAS). HIF1α is ubiquitously expressed, while HIF2α and HIF3α are tissue-specific. HIFs are regulated by prolyl hydroxylases (PHDs), which are oxygen-sensitive enzymes that hydroxylate HIFα, leading to its degradation. Under hypoxia, PHD activity decreases, stabilizing HIFα and promoting the transcription of genes involved in adaptation to low oxygen conditions. HIFα is also regulated by FIH1, an asparaginyl hydroxylase that inhibits HIFα activity by preventing its interaction with coactivators. FIH1 deficiency leads to metabolic phenotypes such as reduced weight, increased insulin sensitivity, and resistance to obesity-related conditions. HIFs are also regulated by mitochondrial activity, which produces reactive oxygen species (ROS) that inhibit PHD activity. Mitochondria sense oxygen deprivation and produce ROS to regulate PHD activity, which in turn affects HIF stability. Sirtuins, a family of NAD+-dependent histone deacetylases, also regulate HIF activity. Sirt1 and Sirt6 modulate HIF2α and HIF1α, respectively, influencing gene expression and metabolic processes. HIFs play essential roles in metabolism, redox homeostasis, and angiogenesis. HIF1α promotes glucose metabolism and reprogramming of cellular energy production, while HIF2α is involved in maintaining redox balance and promoting tumor resistance to radiation. HIFs are also critical in cancer development and progression. HIF1α and HIF2α have distinct roles in tumorigenesis, with HIF2α often associated with more aggressive cancers. HIFs regulate angiogenesis, metastasis, and cancer stem cell maintenance. Mutations in HIF-regulating genes, such as VHL, can lead to HIF stabilization and tumor growth. HIFs also influence inflammatory responses, with HIF1α and HIF2α differentially regulated in immune cells. Overall, HIFs are central to the cellular response to hypoxia and play key roles in metabolism, angiogenesis, and cancer. Understanding HIF regulation is crucial for developing therapeutic strategies targeting hypoxia-related diseases.Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. In mammals, HIFs are heterodimers consisting of an oxygen-sensitive α subunit and a stable β subunit. Three HIFα isoforms exist: HIF1α, HIF2α (also known as EPAS1), and HIF3α (IPAS). HIF1α is ubiquitously expressed, while HIF2α and HIF3α are tissue-specific. HIFs are regulated by prolyl hydroxylases (PHDs), which are oxygen-sensitive enzymes that hydroxylate HIFα, leading to its degradation. Under hypoxia, PHD activity decreases, stabilizing HIFα and promoting the transcription of genes involved in adaptation to low oxygen conditions. HIFα is also regulated by FIH1, an asparaginyl hydroxylase that inhibits HIFα activity by preventing its interaction with coactivators. FIH1 deficiency leads to metabolic phenotypes such as reduced weight, increased insulin sensitivity, and resistance to obesity-related conditions. HIFs are also regulated by mitochondrial activity, which produces reactive oxygen species (ROS) that inhibit PHD activity. Mitochondria sense oxygen deprivation and produce ROS to regulate PHD activity, which in turn affects HIF stability. Sirtuins, a family of NAD+-dependent histone deacetylases, also regulate HIF activity. Sirt1 and Sirt6 modulate HIF2α and HIF1α, respectively, influencing gene expression and metabolic processes. HIFs play essential roles in metabolism, redox homeostasis, and angiogenesis. HIF1α promotes glucose metabolism and reprogramming of cellular energy production, while HIF2α is involved in maintaining redox balance and promoting tumor resistance to radiation. HIFs are also critical in cancer development and progression. HIF1α and HIF2α have distinct roles in tumorigenesis, with HIF2α often associated with more aggressive cancers. HIFs regulate angiogenesis, metastasis, and cancer stem cell maintenance. Mutations in HIF-regulating genes, such as VHL, can lead to HIF stabilization and tumor growth. HIFs also influence inflammatory responses, with HIF1α and HIF2α differentially regulated in immune cells. Overall, HIFs are central to the cellular response to hypoxia and play key roles in metabolism, angiogenesis, and cancer. Understanding HIF regulation is crucial for developing therapeutic strategies targeting hypoxia-related diseases.