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

Apr 5, 2026International immunopharmacology

Bergapten may slow osteoarthritis by boosting cell cleanup and reducing cell death through a key cell growth pathway

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Abstract

Bergapten (BeG) treatment significantly inhibited extracellular matrix degradation and reduced inflammatory mediator expression in mouse primary chondrocytes.

BeG may suppress NLRP3 inflammasome activation and markers associated with cell death (pyroptosis).
Treatment with BeG restored mitochondrial function and enhanced the process of removing damaged mitochondria.
BeG administration in a mouse model reduced cartilage destruction and osteophyte formation.
Intra-articular BeG treatment was associated with improved scores on the Osteoarthritis Research Society International (OARSI) scale.
Inhibition of mitochondrial removal or activation of a specific signaling pathway diminished the protective effects of BeG.

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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.

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

Abstract

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