Piezo1 inhibition by Saikosaponin B1 alleviates mitochondrial damage and apoptosis in osteoarthritic chondrocytes.

Piezo1 is a well-established mechanosensitive ion channel that has been implicated in the progression of osteoarthritis (OA). However, the mechanisms by which Piezo1 contributes to chondrocyte injury within the inflammatory microenvironment, its interplay with mitochondrial dysfunction, and its role in interventions based on natural compounds remain poorly understood. This study investigated the modulatory effects of saikosaponin B1 (SSB1) on Piezo1 and its ability to alleviate mitochondrial damage and apoptosis in osteoarthritic chondrocytes. Through systematic screening of a natural compound library, we identified SSB1 as a potent modulator of Piezo1. In an in vitro inflammatory chondrocyte model, Piezo1 was aberrantly upregulated and hyperactivated, resulting in pathological Ca2⁺ influx, cytosolic calcium overload, and profound mitochondrial dysfunction that ultimately led to chondrocyte apoptosis and matrix degradation, which are hallmark events in OA pathogenesis. SSB1 effectively inhibited Piezo1-mediated Ca2⁺ influx, reduced the mRNA expression of proinflammatory mediators and matrix-degrading enzymes, and increased the expression of type II collagen, a key component of the cartilage matrix. Mechanistically, SSB1 reversed mitochondrial fragmentation, restored mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited the aberrant opening of the mitochondrial permeability transition pore, thereby restoring mitochondrial homeostasis. Furthermore, SSB1 significantly attenuated inflammation-induced chondrocyte apoptosis, an effect associated with the transcriptional inhibition of nuclear factor kappa B (NF-κB) signaling. Collectively, our findings not only reveal the regulatory role of Piezo1 in OA pathology but also establish its potential as a druggable target, providing a promising candidate therapeutic agent for OA treatment.