Glycine induces MafG to regulate glutathione metabolism, inhibit chondrocyte ferroptosis, and upregulate plectin to improve osteoarthritis.

To investigate the mechanism by which glycine inhibits chondrocyte ferroptosis and improves osteoarthritis (OA), primary rat chondrocytes were pre-treated with glycine prior to interleukin-1β (IL-1β) stimulation. Cellular viability, apoptosis, senescence, reactive oxygen species (ROS), lipid peroxide, Fe2+, and GSH level were determined. Transcriptomic analysis, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were employed to confirm the MafG-Plectin regulatory axis. Loss-of-function experiments using siRNA targeting Plectin or MafG validated the functional necessity of this axis. A rat OA model was established by anterior cruciate ligament transection (ACLT), and glycine was injected intra-articularly. Glycine pretreatment significantly improved IL-1β-induced chondrocyte dysfunction, inhibited ROS accumulation, lipid peroxidation, and Fe2+ overload, and upregulated SLC7A11 and GPX4. Glycine upregulated MafG, which directly bound the Plectin promoter to promote Plectin transcription. Silencing of either MafG or Plectin reversed glycine's protective effects, confirming the MafG-Plectin axis as an essential operative module. In OA rats, glycine alleviated cartilage degradation, improved bone microstructure, and upregulated MafG, Plectin, and GPX4; these effects were abolished by si-MafG. Collectively, glycine inhibits chondrocyte ferroptosis and improves OA through a dual mechanism involving MafG-mediated GSH synthesis and MafG-dependent Plectin upregulation, providing a potential therapeutic target for OA.