Salvia miltiorrhiza Bunge alleviates pulmonary fibrosis by promoting fibroblast mitophagy.

Abstract

<p>ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (SM), a traditional medicinal herb, demonstrates potential in treating pulmonary fibrosis (PF). Although preclinical studies suggest anti-fibrotic properties, its mechanisms remain unclear. This study elucidates the efficacy and molecular pathways of SM in pulmonary fibrosis. MATERIALS AND METHODS: A rodent model of pulmonary fibrosis and an in vitro lung fibroblast system were established. RNA sequencing and gene interference were used to investigate the core mechanism of SM action. RESULTS: We found that SM remarkably alleviated pulmonary fibrosis by reducing pulmonary edema and inflammation in PF rats. SM inhibited TGF-β1-induced fibroblast activation and collagen formation. Mechanistically, SM inhibited TGF-β1-induced Smad2/3 signaling. RNA-seq analysis revealed that SM enhanced mitophagy, thereby preserving mitochondrial membrane potential, a process implicated in fibroblast activation. Moreover, we observed that SM activated PINK1/parkin signaling in cultured fibroblasts and in fibroblasts isolated from fibrotic lungs. SM promoted PINK1 spot formation and increased the mitochondrial LC3BII/I ratio. Furthermore, we found that PINK1 knockdown or AKT inhibition weakens the anti-activating effect in fibroblasts. CONCLUSIONS: Taken together, our results showed that SM could alleviate pulmonary fibrosis. SM promotes mitophagy to reduce mitochondrial dysfunction, thereby inhibiting fibroblast activation. These effects of SM may depend on the regulation of AKT/PINK1 signaling. Taken together, we suggest that SM is a substitution therapy for pulmonary fibrosis with a protective effect on mitochondria.</p>