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However, the genetic determinants for initiation and progression of sepsis remain unclear. Here, we showed that the expression levels of estrogen receptor \u03b2 (ER\u03b2) were significantly reduced in the peripheral blood of patients with sepsis and were negatively correlated with disease severity. The results from human samples and experimental animals demonstrated that ER\u03b2 deficiency enhanced the body\u2019s susceptibility to sepsis by inducing macrophage pyroptosis, thereby impairing bacterial clearance. Mechanistically, ER\u03b2 deficiency enhanced fatty acid oxidation, increased acetyl-CoA levels, and promoted acetylation of stomatin-like protein 2 (Stoml2) at K221, leading to mitochondrial dysfunction and macrophage pyroptosis. Mutating the Stoml2 K221 site mitigated these effects and improved survival of septic mice. These findings suggest ER\u03b2 deficiency as a potential genetic factor in sepsis susceptibility.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>ER\u03b2 is a susceptibility gene for sepsis, and its deficiency worsens sepsis outcomes through metabolic reprogramming induced macrophage pyroptosis.<\/jats:p>","DOI":"10.1172\/jci196636","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:00:35Z","timestamp":1773763235000},"source":"Crossref","is-referenced-by-count":3,"title":["Estrogen receptor \u03b2 deficiency increases susceptibility to sepsis through metabolic reprogramming\u2013induced macrophage pyroptosis"],"prefix":"10.1172","volume":"136","author":[{"given":"Yanrong","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 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