Pharmacological regulation of chondrocyte ferroptosis by plant-derived metabolites in osteoarthritis: from molecular mechanisms to targeted nanodelivery

Osteoarthritis (OA) lacks approved disease-modifying pharmacotherapy. Chondrocyte ferroptosis—iron-dependent phospholipid peroxidation caused by disrupted iron handling, lipid metabolism, and antioxidant defense—has been implicated in cartilage degeneration and is pharmacologically suppressible in experimental models. Natural products can modulate multiple ferroptosis-related nodes, including the Nrf2/SLC7A11/GPX4 axis, ACSL4-dependent lipid peroxidation, iron homeostasis, and mitochondrial redox balance. Their translation, however, is limited by poor solubility, instability, rapid clearance, uncertain dose–exposure relationships, and restricted cartilage penetration. This review integrates the pharmacological basis of chondrocyte ferroptosis, evidence for anti-ferroptotic natural products, and nanodelivery strategies that improve joint retention, cartilage targeting, chondrocyte uptake, and controlled release. We distinguish direct ferroptosis evidence from adjacent antioxidant or chondroprotective findings and evaluate polymeric, lipid-based, hydrogel, biomimetic, inorganic, and hybrid platforms as pharmacological optimization tools. Current integrated systems show encouraging structure-preserving effects in experimental OA, but evidence remains predominantly preclinical. Translation will require standardized compounds, ferroptosis-specific target-engagement assays, pharmacokinetic and dose–response studies, carrier-specific safety testing, clinically relevant models, and biomarker-guided patient selection. Rationally matching natural-product pharmacology with joint-specific delivery may enable mechanism-based OA therapies.