Matrix Stiffness Promotes <scp>DRP1</scp> ‐Mediated Myofibroblast Senescence to Drive Silica‐Induced Pulmonary Fibrosis

Silicosis is an occupational lung disease characterized by diffuse pulmonary fibrosis resulting from inhalation of silica particles. As the disease progresses, lung tissue stiffness continuously increases, driving persistent activation and accumulation of myofibroblasts. However, whether these cells undergo senescence in response to prolonged high matrix stiffness and how such senescence impacts fibrosis progression remain unclear. Here, we established an in vitro model using decellularized lung matrices with varying stiffness to simulate the fibrotic mechanical microenvironment. We found that increased matrix stiffness upregulated mitochondrial fission protein DRP1, inducing excessive mitochondrial fragmentation and accumulation of mitochondrial reactive oxygen species (mtROS), leading to oxidative stress, DNA damage, and myofibroblast senescence. Treatment with the mitochondria-targeted antioxidant Mitoquinone mesylate (MitoQ10) effectively alleviated these effects. Moreover, senescent myofibroblast-derived secretions promoted fibroblast activation and collagen deposition via paracrine signaling, exacerbating fibrotic remodeling. These findings identify matrix stiffness-driven cellular senescence as a critical mechanism in silicosis progression, providing a rationale for targeting senescent cells as an antifibrotic therapeutic strategy.