CGRP is essential for protection against alveolar epithelial cell necroptosis by activating the AMPK/L‐OPA1 signaling pathway during acute lung injury

Alveolar epithelial cell (AEC) necroptosis is critical to disrupt the alveolar barrier and provoke acute lung injury (ALI). Here, we define calcitonin gene‐related peptide (CGRP), the most abundant endogenous neuropeptide in the lung, as a novel modulator of AEC necroptosis in lipopolysaccharide (LPS)‐induced ALI. Upon LPS‐induced ALI, overexpression of Cgrp 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‐OPA1) deficiency mediates mitochondrial fragmentation, leading to AEC necroptosis. In this study, we discovered that CGRP positively regulated mitochondrial fusion through stabilizing L‐OPA1. Mechanistically, we elucidate that CGRP activates AMP‐activated 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‐mediated activation of the AMPK/L‐OPA1 axis may have potent therapeutic benefits for patients with ALI or other diseases with necroptosis. Calcitonin gene‐related peptide (CGRP), the most abundant endogenous neuropeptide in the lung, has been identified as a novel modulator of alveolar epithelial cell (AEC) necroptosis in lipopolysaccharide (LPS)‐induced acute lung injury (ALI). CGRP promotes mitochondrial fusion, restores mitochondrial function, and inhibits necroptosis of LPS‐treated AECs by activating the AMPK‐long optic atrophy 1 (L‐OPA1) pathway. This mechanism ultimately contributes to the alleviation of ALI.