cPLA2 in musculoskeletal and autoimmune diseases: Molecular mechanisms and therapeutic insights

Cytosolic phospholipase A2 (cPLA2) is a central regulator of lipid signaling that links cytokine and growth factor signaling to arachidonic acid metabolism and downstream eicosanoid production. Dysregulated cPLA2 activity is increasingly recognized as a shared pathogenic mechanism across musculoskeletal and autoimmune diseases, including osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteoporosis, inflammatory myopathies, sarcopenia and Duchenne muscular dystrophy, as well as inflammatory bowel disease and multiple sclerosis. This review provides a focused and mechanistic overview of cPLA2 biology, emphasizing its regulation by Ca²⁺-dependent membrane translocation and MAPK-mediated phosphorylation, and its cell type specific actions in chondrocytes, osteoblasts, osteoclasts, myocytes, and immune cells. We discuss how cPLA2-driven lipid mediators coordinate inflammation, extracellular-matrix turnover, mitochondrial dysfunction, cellular senescence, and immune cell activation to drive chronic tissue degeneration. Importantly, we summarize emerging therapeutic strategies targeting cPLA2, spanning selective small-molecule inhibitors, gene-editing approaches, and drug repurposing (e.g., pyruvate and fexofenadine), and discuss their translational promise. Collectively, these insights position cPLA2 as a master regulator linking lipid metabolism with inflammation and tissue remodeling and may provide a unifying framework for developing disease-modifying therapies across diverse inflammatory and degenerative conditions, particularly musculoskeletal and autoimmune disorders.