Signal-driven interplay between lipid peroxidation and ferroptosis orchestrates osteoarthritis degeneration.

UNLABELLED: Osteoarthritis (OA) is progressively documented as a whole-joint disorder in which oxidative stress, iron dysregulation and intercellular communication together drive progressive tissue degeneration. Among the chief oxidative mechanisms, lipid peroxidation has arisen as a critical contributor to cartilage destruction and inflammatory signalling cascade. Reactive aldehydes produced during lipid peroxidation, mainly malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE), function as electrophilic mediators that change signalling pathways, extracellular matrix components and proteins, including NF-κB and MAPK. Persistent oxidative stress converges on ferroptosis, an iron-dependent form of regulated cell death characterized by impaired GPX4 activity, lipid peroxide accumulation and glutathione depletion. Ferroptotic chondrocytes also amplify osteoarthritic progression by releasing matrix-degrading enzymes and inflammatory cytokines that impact neighbouring osteoclasts, osteoblasts and synoviocytes. Additionally, mechanical stress contributes to this pathological network through Piezo1/TRPV4-mediated mechanotransduction, connecting aberrant biomechanical loading to intracellular calcium imbalance, ferroptosis activation and iron accumulation. Accumulative evidence specifies that dysregulated iron homeostasis plays a dual role in OA pathogenesis, as iron overload promotes reactive oxygen species generation through Fenton chemistry, whereas iron deficiency impairs antioxidant defence and osteogenesis mechanisms. Therapeutically, biomaterial-based nano-delivery systems, antioxidant compounds, iron chelators, and ferroptosis-targeted interventions have confirmed potential in restoring redox balance and suppress OA-associated inflammation. Cerium oxide, selenium, and MnO2 nanozymes, together with smart intra-articular delivery platforms, provide targeted reactive oxygen species scavenging and improve therapeutic localization within inflamed joints. By integrating mechanotransduction, iron metabolism, ferroptosis and lipid peroxidation, inter-tissue communication into a unified mechanistic framework, this review highlights emerging diagnostic biomarkers and translational strategies for the development of disease-modifying therapies in osteoarthritis.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review proposes an effective cascade mechanism wherein mechanical and inflammatory stimulation results in iron deregulation, lipid peroxidation, ferroptosis, and finally the development of osteoarthritis. The assessment of biomarkers related to ferroptosis such as MDA, 4 HNE adducts, labile iron, and GPX4 enzymatic activities can be useful for stratifying early-stage osteoarthritis and monitoring the disease. Meanwhile, antioxidant molecules, iron chelating compounds, and nanotechnology-based intraarticular drug delivery systems represent promising strategies for the prevention of osteoarthritis development.