Significance of Necroptosis in Cartilage Degeneration

Cartilage, an essential tissue for joint function, is prone to degeneration caused by conditions such as osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Emerging research highlights necroptosis—a regulated form of necrosis—as a critical contributor to cartilage degradation. Unlike apoptosis, necroptosis induces strong inflammatory responses, amplifying tissue damage. Key mediators in this process include receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL). Studies demonstrate that necroptosis plays a significant role in OA and RA pathogenesis, with elevated levels of RIPK3 and related proteins driving cartilage breakdown.

Therapeutic strategies targeting necroptotic pathways show promise, with inhibitors such as Necrostatin-1 (Nec-1), GSK’872, and Necrosulfonamide (NSA) effectively reducing necroptotic cell death. Furthermore, the protective role of autophagy in mitigating necroptosis-induced damage underscores the importance of integrated approaches that address multiple molecular pathways. While these findings provide valuable insights, further research is needed to fully elucidate the mechanisms of necroptosis and to translate these discoveries into effective treatments. This review consolidates current understanding of necroptosis in cartilage degeneration, aiming to guide the development of novel therapies for OA, RA, and trauma-related cartilage damage.