Targeting the osteoimmune microenvironment to prevent regulated chondrocyte death in osteoarthritis: therapeutic potential of natural products.

Osteoarthritis (OA) is increasingly recognized as a whole-joint disease driven by a dysregulated osteoimmune microenvironment, rather than mere mechanical wear. Despite the high prevalence of OA, current pharmacotherapies are largely palliative, failing to halt cartilage degeneration or reverse chondrocyte death. Consequently, the development of Disease-Modifying Osteoarthritis Drugs (DMOADs) targeting the underlying pathology remains an urgent unmet need. Natural products, distinguished by their pleiotropic nature, have emerged as promising candidates capable of functioning as "network regulators" to restore joint homeostasis. This review systematically elucidates the multi-dimensional mechanisms by which natural products prevent regulated cell death (RCD) in chondrocytes. We highlight their capacity to orchestrate upstream immune responses by repolarizing synovial macrophages, blocking inflammatory cascades (e.g., NLRP3 inflammasome), and restoring downstream cellular defenses. Special attention is given to emerging mechanisms, including the inhibition of ferroptosis and the reversal of metabolic reprogramming via the modulation of the HIF-1α/HIF-2α switch and the NAD+/SIRT1 axis. Furthermore, we extend the discussion to the subchondral bone, emphasizing the restoration of the osteochondral unit. To bridge the gap between preclinical success and clinical translation, we discuss current challenges such as bioavailability and propose future strategies involving biomimetic nanodelivery systems and precision medicine based on OA endotypes. Collectively, this review provides a comprehensive framework for utilizing natural products to rewire the osteoimmune microenvironment, highlighting their potential as promising candidates for future DMOAD development.