Kumatakenin alleviates LPS-induced acute lung injury by attenuating pulmonary oxidative stress and neutrophil extracellular trap formation through CMA-associated regulation of PRL2.

Abstract

Acute lung injury (ALI) is a life-threatening inflammatory syndrome with limited pharmacological treatment options. Kumatakenin, a plant-derived flavonoid with recognized anti-inflammatory potential, has not been explored in inflammatory lung injury. Here, we investigated the protective effect of Kumatakenin in lipopolysaccharide (LPS)-induced ALI and examined the associated mechanism. Kumatakenin markedly alleviated lung injury, as evidenced by improved histopathology, reduced pulmonary edema, and decreased inflammatory cytokine production. It also attenuated neutrophil accumulation and activation in the lung, accompanied by suppression of neutrophil extracellular trap formation and oxidative stress. Mechanistically, Kumatakenin increased PRL2 protein abundance without altering its mRNA expression, suggesting post-transcriptional regulation. This effect was associated with reduced CMA-related PRL2 turnover, as indicated by decreased LAMP2A expression and weakened interaction of PRL2 with Hsc70 and LAMP2A. Moreover, pharmacological activation of CMA with QX77 largely reversed the effects of Kumatakenin on PRL2 protein abundance, oxidative stress, and NET formation. Collectively, these findings indicate that Kumatakenin alleviates LPS-induced ALI by interrupting neutrophil-driven inflammatory amplification and, at least in part, suppressing CMA-associated PRL2 degradation. This study highlights Kumatakenin as a promising natural lead compound for inflammatory lung disorders and identifies the CMA/PRL2 axis as a candidate therapeutic pathway.