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

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ID: 317979
2026
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Abstract
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 (SLE), rheumatoid arthritis (RA), 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.
Reference Key
openalex_W7165205367 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Dongye Li, Xihao Pan, Zijin He, Jingru Cui, Runhe Zhu, Dadong Guo
Journal journal of leukocyte biology
Year 2026
DOI
10.1093/jleuko/qiag082
URL
https://doi.org/10.1093/jleuko/qiag082
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