Glycolytic metabolic reprogramming and mitochondrial dysfunction: A novel mechanism underlying PAEs-promoted...

Phthalate esters (PAEs), the most prevalent class of plasticizers, are widely acknowledged as environmental endocrine disruptors (EDCs) and have been linked to the pathogenesis of various diseases. However, their specific role and intrinsic mechanism in inducing cartilage damage in bone-related diseases remain unclear. This study aimed to clarify the correlation between PAEs and cartilage damage, and to explore their potential molecular mechanisms. The core pathological change of knee osteoarthritis (KOA) is the progressive degeneration of articular cartilage. Based on this, this study first systematically explored the association between PAEs and KOA using network toxicology combined with molecular docking technology, and screened out core regulatory molecules including MMP9, EGFR, IL-10, BCL2, and CASP3. Subsequently, verification experiments on core molecules showed that PAEs exposure could activate the CASP3 pathway to induce apoptosis of human chondrocytes and significantly promote the formation of the inflammatory phenotype of chondrocytes. To further reveal the underlying mechanism, we conducted proteomic analysis and cell experiments in human articular chondrocytes (HCs). The results showed that exposure to PAEs triggered reprogramming of glycolysis metabolism, inhibited oxidative phosphorylation, and damaged mitochondrial homeostasis. Collectively, this study provides a robust theoretical basis for understanding the inflammatory phenotypes and underlying mechanisms of chondrocyte damage driven by PAEs exposure, and further lays a foundation for the design of novel therapeutic interventions and the optimization of environmental toxicity assessment protocols targeting PAEs.