Curcumin as a natural therapeutic agent for osteoarthritis: molecular mechanisms, preclinical evidence, clinical applications, and future perspectives.

Osteoarthritis is a prevalent and progressive musculoskeletal disorder characterized by a complex interplay of mechanical stress, low-grade inflammation, oxidative stress, extracellular matrix degradation, chondrocyte dysfunction, and subchondral bone remodeling. Current pharmacological and surgical approaches primarily provide symptomatic relief and have limited capacity to modify the underlying structural progression of the disease. Curcumin, a major bioactive polyphenol derived from Curcuma longa, has attracted considerable interest as a potential therapeutic candidate because of its ability to influence multiple interconnected pathways involved in osteoarthritis pathogenesis. Unlike many phytochemicals investigated primarily through single mechanistic targets, curcumin has been extensively studied for its coordinated effects on inflammatory signaling, oxidative stress, apoptosis, extracellular matrix turnover, and cellular homeostasis. This review critically examines the molecular mechanisms, preclinical evidence, clinical findings, pharmacokinetic limitations, and emerging delivery strategies associated with curcumin in osteoarthritis. Particular emphasis is placed on the relationship between curcumin's multitarget pharmacology and its translational limitations, including poor aqueous solubility, low systemic bioavailability, rapid metabolism, variability among formulations, and heterogeneity of clinical studies. Evidence from experimental models supports anti-inflammatory, antioxidant, chondroprotective, and tissue-preserving effects, whereas clinical studies mainly indicate potential benefits for pain and functional outcomes. However, current evidence remains insufficient to establish curcumin as a disease-modifying therapy. Recent advances in nanotechnology, lipid-based systems, targeted delivery, and curcumin analogues may improve exposure and therapeutic efficacy, although their clinical translation remains to be established. Overall, curcumin represents a biologically plausible multitarget candidate for osteoarthritis, but larger, well-designed, standardized clinical trials incorporating structural and molecular endpoints are required to determine its therapeutic and disease-modifying potential.