Regulated Cell Death Pathways in Chondrocytes During Septic Arthritis: Current Evidence and Future Perspectives.

Septic arthritis is an orthopaedic emergency that rapidly destroys articular cartilage, and its incidence has increased in recent decades. Despite prompt joint drainage and antimicrobial therapy, progressive cartilage loss and joint dysfunction often persist, highlighting the need for strategies that preserve chondrocyte viability. Based on supportive evidence from other organ systems and non-infectious orthopaedic inflammation, chondrocyte fate in septic arthritis may reflect a multimodal landscape of regulated cell death (RCD) that could be therapeutically leveraged. This narrative review synthesizes mechanistic evidence from two complementary domains of septic arthritis biology: Staphylococcus aureus-driven RCD programs reported in infected joints and extra-articular tissues, and chondrocyte RCD mechanisms established in non-infectious arthritis, particularly osteoarthritis and rheumatoid arthritis. The evidence is organized around four canonical RCD modalities-apoptosis, necroptosis, pyroptosis, and ferroptosis-and their shared upstream stress signals linking infection, inflammation, and metabolic injury to cell-death execution. Direct cartilage-focused studies in septic arthritis suggest that apoptosis-associated processes may contribute to chondrocyte death, whereas evidence for necroptosis, pyroptosis, and ferroptosis in infected chondrocytes remains limited. By integrating direct and indirect evidence, we present a conceptual RCD framework in which crosstalk among multiple RCD pathways may sustain cartilage injury even after bacterial clearance. Short-term, locally delivered adjunctive therapies targeting selected RCD pathways after effective infection control may therefore help limit chondrocyte loss and cartilage collapse. Future priorities include direct pathway validation in infected cartilage, development of RCD-related biomarkers, and evaluation of appropriately timed host-directed interventions to improve long-term joint outcomes.