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Here, we define calcitonin gene\u2010related peptide (CGRP), the most abundant endogenous neuropeptide in the lung, as a novel modulator of AEC necroptosis in lipopolysaccharide (LPS)\u2010induced ALI. Upon LPS\u2010induced ALI, overexpression of <jats:italic>Cgrp<\/jats:italic> significantly mitigates the inflammatory response, alleviates lung tissue damage, and decreases AEC necroptosis. Similarly, CGRP alleviated AEC necroptosis under the LPS challenge in vitro. Previously, we identified that long optic atrophy 1 (L\u2010OPA1) deficiency mediates mitochondrial fragmentation, leading to AEC necroptosis. In this study, we discovered that CGRP positively regulated mitochondrial fusion through stabilizing L\u2010OPA1. Mechanistically, we elucidate that CGRP activates AMP\u2010activated protein kinase (AMPK). Furthermore, the blockade of AMPK compromised the protective effect of CGRP against AEC necroptosis following the LPS challenge. Our study suggests that CRGP\u2010mediated activation of the AMPK\/L\u2010OPA1 axis may have potent therapeutic benefits for patients with ALI or other diseases with necroptosis.<\/jats:p>","DOI":"10.1002\/jcp.31169","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T10:04:12Z","timestamp":1704794652000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["CGRP is essential for protection against alveolar epithelial cell necroptosis by activating the AMPK\/L\u2010OPA1 signaling pathway during acute lung injury"],"prefix":"10.1002","volume":"239","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4858-544X","authenticated-orcid":false,"given":"Hui\u2010Ling","family":"Jiang","sequence":"first","affiliation":[{"name":"Immunotherapy Laboratory, College of Pharmacology Southwest Minzu University Chengdu Sichuan China"},{"name":"Department of Physiology, School of Basic Medical Science 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