Phosphatidylethanolamine Alleviates Osteoarthritis Progression by Inhibiting Oxidative Stress-Induced Chondrocyte Ferroptosis in a Lysosomal-Dependent Manner

Purpose: Lysosomal dysfunction and chondrocyte ferroptosis are pivotal drivers of osteoarthritis (OA) pathogenesis, yet their interlinked molecular mechanisms remain poorly defined. This study investigates the associations between lysosomal dysfunctions and ferroptosis in OA chondrocytes, aiming to identify actionable therapeutic targets. Patients and Methods: Human OA cartilage samples were categorized into intact and damaged groups based on structural integrity. Lysosomal fractions were isolated from both groups for comparative lipidomic profiling and functional assays. A rat OA model was established via anterior cruciate ligament transection, followed by histopathological evaluation using hematoxylin-eosin (HE) staining, Safranin-O Fast Green scoring, and immunohistochemical analysis to quantify cartilage repair and degeneration. Results: The damaged groups displayed significantly increased lysosomal membrane permeability (LMP) and ferroptosis activation compared to intact groups. Lysosomal lipidomics revealed oxidative stress-induced down-regulation of phosphatidylethanolamine (PE), a key membrane-stabilizing phospholipid, in chondrocytes. Functional studies demonstrated that PE supplementation rescued chondrocyte viability (CCK-8 assay) and attenuated LMP-driven ferroptosis by restoring lysosomal integrity and suppressing lipid peroxidation. In vivo, intra-articular PE administration markedly reduced OA progression, as evidenced by improved cartilage histology scores, and downregulated ferroptosis markers. Conclusion: PE supplementation restores lysosomal PE levels, reduces LMP, and alleviates ferroptotic phenotypes in preclinical models, suggesting therapeutic potential. These findings significantly increase our understanding of the pathogenesis of OA and reveal potential therapeutic targets for its management.