Research progress of cuproptosis, ferroptosis, apoptosis, and autophagy in knee osteoarthritis.

Knee osteoarthritis (KOA) is a highly prevalent chronic degenerative joint disorder characterized by progressive articular cartilage degeneration, chondrocyte death, and extracellular matrix degradation. Accumulating evidence indicates that dysregulated programmed cell death (PCD) pathways-including cuproptosis, ferroptosis, and apoptosis-along with autophagic dysfunction play pivotal roles in KOA pathogenesis. Cuproptosis is a recently identified copper-dependent cell death modality triggered by mitochondrial copper overload, leading to aggregation of lipoylated TCA cycle enzymes, destabilization of iron-sulfur clusters, and proteotoxic stress. Ferroptosis is an iron-dependent regulated cell death pathway driven by lethal lipid peroxidation and GPX4 inactivation. Apoptosis, the classical caspase-dependent PCD, contributes to chondrocyte loss through extrinsic and intrinsic pathways. Autophagy exhibits a context-dependent dual role, serving cytoprotective functions under physiological conditions yet becoming detrimental when dysregulated. Importantly, these pathways exhibit marked stage-dependent and cell-type-specific characteristics during KOA progression: their activity profiles differ substantially between early, middle, and advanced disease, and among chondrocytes, synovial fibroblasts, macrophages, and subchondral bone cells. These four processes engage in intricate crosstalk through shared molecular nodes, including ROS, GSH metabolism, mitochondrial dynamics, and mTOR/NF-κB signaling. This review provides a comprehensive synthesis of the core molecular mechanisms, critically evaluates the stage-dependent and cell-type-specific roles in KOA pathogenesis, and systematically maps the crosstalk network with causal relationships. We also discuss current therapeutic strategies (metal chelators, natural compounds, nanoparticle systems) with detailed assessment of their mechanisms, limitations, and translational bottlenecks, and propose future research directions for developing multi-target disease-modifying osteoarthritis drugs (DMOADs). Specific clinical implications-including biomarker potential, patient stratification, and stage-guided personalized therapy-are also highlighted.