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This study investigated the role of estrogen-related receptor \u03b1 (ERR\u03b1) in SABD pathogenesis using ERR\u03b1 knockout (KO) mice and cecal ligation and puncture (CLP) models. We found that ERR\u03b1 KO mice exhibited improved survival rates, milder neurological symptoms, reduced pro-inflammatory cytokine production (TNF-\u03b1, IL-1\u03b2), and increased anti-inflammatory cytokine (IL-10) levels compared to wild-type controls. Additionally, ERR\u03b1 deficiency promoted microglial M2 polarization and attenuated ferroptosis, as evidenced by decreased iron accumulation, reduced lipid peroxidation, and normalized mitochondrial morphology. Mechanistically, these protective effects were mediated through inhibition of the NF-\u03baB signaling pathway. In vitro studies with ERR\u03b1 knockdown in LPS-stimulated BV2 microglia confirmed these findings. Our results suggest that ERR\u03b1 as a critical regulator of microglial function in SABD through coordinated control of inflammatory responses, polarization states, and ferroptosis, suggesting that targeting ERR\u03b1 may represent a promising therapeutic strategy for SABD treatment.<\/jats:p>","DOI":"10.1007\/s12035-025-05005-1","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T22:08:03Z","timestamp":1746482883000},"page":"11834-11847","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["ERR\u03b1 Knockout Promotes M2 Microglial Polarization and Inhibits Ferroptosis in Sepsis-Associated Brain Dysfunction"],"prefix":"10.1007","volume":"62","author":[{"given":"Jun","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingshan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Yan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jie","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"5005_CR1","doi-asserted-by":"publisher","unstructured":"Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M,... 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