HIF-1α in macrophage polarization: roles in immunometabolism and autoimmune diseases.

Hypoxia-inducible factor-1α (HIF-1α) is a central regulator of cellular responses to hypoxia and plays a pivotal role in immune cell activation and functional reprogramming. This review summarizes how HIF-1α modulates inflammatory responses through metabolic regulation and examines its mechanistic involvement in autoimmune diseases. Under normoxic conditions, HIF-1α is rapidly degraded, whereas hypoxia, inflammation, or metabolic stress stabilizes the protein, allowing its nuclear translocation and activation of glycolysis-related genes. This shift drives immune cells from oxidative metabolism to glycolysis, supporting rapid energy production and promoting inflammation-associated functional states. Consequently, HIF-1α enhances the production of inflammatory mediators and forms positive feedback loops with inflammatory signaling pathways, influencing immune cell migration, survival, and function. Aberrant activation of HIF-1α is closely associated with disease activity in autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, contributing to immune imbalance and tissue damage. However, its effects are context-dependent; in conditions like inflammatory bowel disease and uveitis, moderate activation may exert protective roles. Therefore, therapeutic strategies require precise, context-specific modulation rather than simple inhibition or activation. Although current drug development targeting HIF-1α focuses mainly on oncology, emerging approaches-including small molecule inhibitors, nanodelivery systems, and gene therapy-highlight its potential in autoimmune disease treatment. Overall, HIF-1α serves as a key link between hypoxia, metabolism, and immune regulation.