Polystyrene microplastics drive chondrotoxicity in osteoarthritis through inducing ER stress and apoptosis via NFKB1 activation.

Polystyrene microplastics (PS-MPs), recognized as widespread environmental contaminants, have been identified within human articular tissues. However, their contribution to the pathogenesis of osteoarthritis (OA) remains incompletely understood. In this study, a combination of network toxicology and transcriptomic profiling was employed to pinpoint 30 core targets implicated in PS-MP-induced OA. Functional enrichment analyses indicated significant associations with inflammatory processes, endoplasmic reticulum (ER) stress, and apoptotic pathways. Through machine learning algorithms, six potential diagnostic biomarkers for early-stage OA were identified. Among these, NFKB1 emerged as a core target, with both molecular docking and dynamic simulations confirming its stable interaction with PS-MPs. Subsequent in vitro assays and single-cell RNA sequencing revealed that PS-MPs upregulate NFKB1 expression, thereby intensifying inflammation, ER stress, and chondrocyte apoptosis. Notably, pharmacological inhibition of NFKB1 using MD-1 mitigated these deleterious effects and preserved extracellular matrix integrity. These findings elucidate a mechanistic pathway by which PS-MPs contribute to OA progression through NFKB1-driven ER stress and apoptosis, providing novel perspectives on environmentally induced OA pathology and identifying a potential therapeutic target for countering PS-MP-related chondrotoxicity.