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This review summarizes how HIF-1\u03b1 modulates inflammatory responses through metabolic regulation and examines its mechanistic involvement in autoimmune diseases. Under normoxic conditions, HIF-1\u03b1 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-1\u03b1 enhances the production of inflammatory mediators and forms positive feedback loops with inflammatory signaling pathways, influencing immune cell migration, survival, and function.<\/jats:p>\n                  <jats:p>Aberrant activation of HIF-1\u03b1 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-1\u03b1 focuses mainly on oncology, emerging approaches\u2014including small molecule inhibitors, nanodelivery systems, and gene therapy\u2014highlight its potential in autoimmune disease treatment. Overall, HIF-1\u03b1 serves as a key link between hypoxia, metabolism, and immune regulation.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag082","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:21:27Z","timestamp":1781695287000},"source":"Crossref","is-referenced-by-count":1,"title":["HIF-1\u03b1 in macrophage polarization: roles in immunometabolism and autoimmune diseases"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0200-3581","authenticated-orcid":false,"given":"Dongye","family":"Li","sequence":"first","affiliation":[{"name":"College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2603-2360","authenticated-orcid":false,"given":"Xihao","family":"Pan","sequence":"additional","affiliation":[{"name":"College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZiJin","family":"He","sequence":"additional","affiliation":[{"name":"College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3555-4373","authenticated-orcid":false,"given":"Jingru","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runhe","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250013 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