Kaempferol Alleviates Acrolein‐Induced Lung Injury In Vitro and In Vivo by Binding to Peli2 and Disrupting the Peli2‐NLRP3 Interaction

Acrolein (ACR) is a highly toxic agent that induces lung inflammation and causes acute lung injury (ALI). However, effective treatments for ACR‐induced ALI are currently lacking. We investigated the protective effects of kaempferol (Kae) against ACR‐induced ALI using in vitro (HBE and BEAS‐2B cells) and in vivo murine models (male C57BL/6 mice). Molecular docking, surface plasmon resonance (SPR), immunoprecipitation, and ubiquitination assays were performed to elucidate the underlying mechanisms. In vitro, Kae (30 µM) significantly reversed ACR (30 µM)‐induced cytotoxicity, restoring cell viability to control levels, and reduced LDH release by 48.3% and 41.7%, respectively, in the two cell lines. Kae suppressed ACR‐triggered ROS generation by approximately 66%, apoptosis from 50.96% to 18.3% in BEAS‐2B cells, and pro‐inflammatory cytokine production (IL‐1β, IL‐6, TNF‐α, iNOS, COX‐2). In vivo, Kae pre‐treatment (30 mg/kg) attenuated ACR (10 mg/kg)‐induced ALI, reducing histopathological lung injury score by 62.5%, decreasing TNF‐α and IL‐1β levels by 54.2% and 49.7%, respectively, and inhibiting NF‐κB activation. Mechanistically, Kae binds to the FHA domain of Peli2 and promotes its ubiquitination and degradation, resulting in the disruption of the Peli2‐NLRP3 interaction and inhibition of NLRP3 inflammasome activation. Our findings confirm that Peli2 is a novel therapeutic target for ALI, and Kae is a promising candidate for treating ACR‐induced ALI.