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This review systematically delineates SAID pathophysiology, evaluates preclinical and clinical evidence for autophagy\u2010targeted interventions, and explores emerging intestinal\u2010specific therapeutic targets. Autophagy preserves intestinal barrier integrity by clearing damaged organelles and suppressing NLRP3 inflammasome activation, whereas inflammatory mediators such as TNF\u2010\u03b1\/IL\u20106 and reactive oxygen species impair autophagic flux via Beclin\u20101 destabilization and lysosomal dysfunction, establishing a pathogenic vicious cycle. Preclinical evidence demonstrates that rapamycin and TFEB agonists enhance autophagy, while ATG5 overexpression and NLRP3 siRNA restore epithelial homeostasis. Clinically, IL\u20101 receptor antagonists have demonstrated efficacy in specific sepsis subpopulations. Stage\u2010specific therapeutic optimization is essential, as interventions must be tailored to the hyperinflammatory versus immunoparalysis phases. Novel intestinal\u2010barrier\u2010specific targets\u2014including aquaporin\u20103 (AQP3), ghrelin, and Nur77\u2014emerge as key regulators of the autophagy\u2212inflammation axis and represent promising therapeutic candidates. Targeting autophagy\u2212inflammation crosstalk holds significant therapeutic potential, though clinical translation requires human\u2010relevant models and precision medicine approaches to address disease heterogeneity and stage\u2010specific pathophysiology.<\/jats:p>","DOI":"10.1111\/nyas.70243","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:23:21Z","timestamp":1773663801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms of Autophagy and Inflammatory Response Crosstalk in Sepsis\u2010Associated Intestinal Dysfunction"],"prefix":"10.1111","volume":"1557","author":[{"given":"He","family":"Man","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, People's Hospital of Suzhou New District  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Yi","sequence":"additional","affiliation":[{"name":"Department 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