Farrerol inhibits ferroptosis and protects against LPS-induced acute lung injury by targeting the RUNX1/SLC7A11 axis.

INTRODUCTION: Acute lung injury (ALI) is a critical condition with diverse etiologies, characterized by high mortality rates and a lack of specific therapeutic interventions. Farrerol, a naturally occurring flavonoid isolated from Rhododendron spp., exhibits potent anti-inflammatory and antioxidant activities. Previous studies have indicated that farrerol exerts protective effects against lipopolysaccharide (LPS)-induced ALI; however, the underlying mechanisms remain elusive. This study aimed to elucidate the protective mechanisms of farrerol against LPS-induced ALI. METHODS: We evaluated the efficacy of farrerol using both in vitro (LPS-stimulated BEAS-2B cells) and in vivo (LPS-induced ALI in mice) models. The protective mechanism of rhododendron against ALI was investigated using proteomics, cellular thermal shift assays, co-immunoprecipitation, and molecular docking. RESULTS: Pretreatment with farrerol significantly improved cell viability and reduced lactate dehydrogenase release in LPS-induced BEAS-2B cells. In vivo, farrerol effectively alleviated LPS-induced pulmonary edema and histopathological damage in mice. Mechanistically, we found that farrerol directly binds to and stabilizes runt-related transcription factor 1 (RUNX1), thereby transcriptionally activating the expression of solute carrier family 7 member 11. Overexpression of RUNX1 mimicked the protective effects of farrerol, while knockdown of RUNX1 abolished these effects. DISCUSSION: Farrerol could directly bind and stabilize the expression of RUNX1, thereby enhancing SLC7A11 transcription and ultimately inhibiting ferroptosis. Thus, farrerol is a potential therapeutic agent for ALI.