Osteoarthritis pathogenesis Unveiled: DMT1 drives autophagy-dependent ferroptosis through a mir-17-5p/NEDD4 regulatory axis

Background: Osteoarthritis (OA), a debilitating joint disorder lacking disease-modifying therapies, involves ferroptosis-an iron-dependent cell death. While ferroptosis contributes to OA progression, its autophagy-dependent mechanisms remain undefined. This study reveals DMT1 (divalent metal transporter 1) as a central regulator of autophagic ferroptosis in OA pathogenesis. Methods: OA-related ferroptosis genes were screened by LASSO regression and random forest models. IL-1β/Erastin-stimulated chondrocytes and DMM-induced OA mice were used to investigate DMT1 function. Ferroptosis and autophagy were assessed by lipid peroxidation, autophagic flux, Western blot, and modulators. Micro-CT, OARSI scoring and behavioral tests evaluated joint damage. Regulatory mechanisms were examined by miR-17-5p mimic, luciferase assays and NEDD4-mediated ubiquitination. Results: DMT1 was upregulated in OA cartilage and IL-1β-stimulated chondrocytes, correlating with ferroptosis activation. Genetic DMT1 suppression attenuated ferroptosis in vitro and in vivo, whereas overexpression exacerbated lipid peroxidation and impaired cartilage repair post-DMM surgery in mice. Mechanistically, DMT1 overexpression activated autophagy, linking it to ferroptosis execution – pharmacological autophagy inhibition reduced DMT1-driven ferroptosis, while autophagy inducers amplified its effects. Conclusions: We identified a DMT1–autophagy–ferroptosis axis as a critical OA mechanism. Ferroptosis inhibitors and upstream regulators (miR-17-5p, NEDD4) show promise as disease-modifying strategies for OA. The translational potential of this article: This study not only elucidates a novel DMT1-autophagy-ferroptosis axis but also identifies NEDD4 as upstream therapeutic targets. The demonstration that Lip-1 treatment alleviates DMT1-driven OA exacerbation in vivo highlights translational potential of ferroptosis inhibition as a disease-modifying strategy for OA. Moreover, NEDD4 overexpression represents promising gene-based interventions with potential for precision therapy in OA.