Sesamin attenuates LPS-induced acute lung injury via inhibiting RASD1-mediated inflammation and epithelial damage

Acute Lung Injury (ALI) involves severe pulmonary inflammation and epithelial damage. Although sesamin exhibits anti-inflammation effects, its underlying mechanism remains unclear. Here, we investigated the protective effects of sesamin and explored its molecular targets in LPS-induced ALI. Sesamin alleviates LPS-induced lung injury by reducing inflammatory cell infiltration and suppressing pro-inflammatory cytokines. Mechanistically, sesamin inhibits RASD1 expression and RASD1 overexpression abolishes its protective effects, identifying RASD1 as a novel mediator of LPS-induced epithelial damage. Molecular docking and molecular dynamics simulations predicted POU2F2 as a high-affinity target of sesamin. Sesamin enhanced RASD1 expression through modulation of POU2F2 transcriptional activity, while mutation of the POU2F2 binding site in the RASD1 promoter eliminated sesamin-mediated transcriptional repression. Collectively, these findings reveal a novel POU2F2–RASD1 signaling axis through which sesamin mitigates LPS-induced inflammation and epithelial injury, highlighting sesamin as a promising therapeutic candidate for ALI. • Sesamin alleviates LPS-induced acute lung injury in both in vivo and in vitro . • Sesamin preserves epithelial barrier and lowers pro-inflammatory cytokines. • Sesamin boosts POU2F2 activity to promote RASD1 and reduce inflammation. • The POU2F2–RASD1 axis is a potential therapeutic target for ALI.