Bergapten ameliorates osteoarthritis progression by inhibiting the PI3K/AKT/mTOR pathway to activate mitophagy and suppress pyroptosis.

Abstract

Osteoarthritis (OA) is a frequently occurring degenerative joint condition involving progressive loss of cartilage integrity accompanied by prolonged inflammatory activity within the joint. Current therapies mainly alleviate symptoms without halting disease progression. This study was designed to assess the pharmacological efficacy of bergapten (BeG), a naturally derived furanocoumarin, in osteoarthritis and to clarify its molecular mechanisms of action. In IL-1β-stimulated mouse primary chondrocytes, BeG treatment significantly inhibited extracellular matrix degradation, suppressed the expression of inflammatory mediators (IL-1β, IL-6, COX-2, iNOS) and reduced NLRP3 inflammasome activation and pyroptosis-related markers (GSDMD-NT, cleaved caspase-1). BeG also restored mitochondrial function, enhanced PINK1/Parkin-mediated mitophagy, and downregulated the PI3K/AKT/mTOR pathway. Pharmacological inhibition of mitophagy (Mdivi-1) or activation of PI3K (740Y-P) abolished these protective effects. In a murine destabilization of the medial meniscus (DMM) model, intra-articular administration of BeG attenuated cartilage destruction, reduced osteophyte formation, and lowered OARSI scores, accompanied by enhanced mitophagy and suppressed pyroptosis in joint tissues. Collectively, our findings demonstrate that BeG mitigates OA progression by inhibiting the PI3K/AKT/mTOR pathway, promoting mitophagy, and subsequently suppressing NLRP3-mediated pyroptosis, underscoring its promise as a disease-modifying osteoarthritis therapeutic.