Sirt1 overexpression inhibits chondrocyte ferroptosis via Ftl deacetylation to suppress the development of osteoarthritis.

Abstract

Introduction: Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by an imbalance in chondrocyte metabolism. Ferroptosis has been implicated in the pathogenesis of OA. The role of Sirt1, a deacetylase, in mediating deacetylation during ferroptosis in OA chondrocytes remains underexplored. This study aimed to elucidate the mechanisms by which Sirt1 influences chondrocyte ferroptosis in the development of OA.

Materials and methods: In vitro and in vivo models of OA were established using IL-1β-induced mouse chondrocytes and a destabilization of the medial meniscus (DMM) mouse model, respectively. Ferroptosis was evaluated through measurements of cell viability, lactate dehydrogenase (LDH) release, intracellular levels of Fe2+, glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (ROS), propidium iodide staining, and Western blot analysis. The underlying mechanisms were further investigated using quantitative real-time polymerase chain reaction, Western blotting, immunoprecipitation (IP), co-immunoprecipitation (Co-IP), and glutathione-S-transferase pulldown assays. In vivo validation was performed via Safranin O staining.

Results: IL-1β induced ferroptosis and increased histone acetylation, effects that were partially reversed by Sirt1 overexpression. Mechanistically, Sirt1 overexpression upregulated ferritin light polypeptide (Ftl) expression by deacetylating Ftl at the K181 residue. Ftl knockdown inhibited the ferroptosis-enhancing effect of Sirt1 overexpression in chondrocytes. In vivo studies showed that Sirt1 overexpression mitigated the progression of OA and reduced ferroptosis in the DMM-induced OA mouse model.

Conclusion: Our findings confirm that Sirt1 overexpression promotes Ftl expression through deacetylation at the K181 site, thereby suppressing chondrocyte ferroptosis and attenuating the progression of OA. These results suggest a potential therapeutic target for OA treatment.