Quercetin Suppresses Ferroptosis in Chondrocytes via Activating the Nrf2/ GPX4 Signaling Pathway

Abstract

Background: Osteoarthritis is a progressive chronic disease that lacks effective treatment strategies. Ferroptosis features may be involved in the development and progression of osteoarthritis. Quercetin, a widely studied flavonoid compound, is considered a potential candidate for osteoarthritis therapies, although its anti-ferroptosis effect remains uncertain. This research aimed to investigate the regulatory impact of quercetin on ferroptosis and Nrf2 signaling in RSL3-induced C28/I2 cells. Methods: Cell viability was measured using the CCK-8 assay. Cellular lipid reactive oxygen species (ROS) were detected using fluorescence microscopy and flow cytometry combined with C11-BODIPY 581/591 staining. The level of malondialdehyde (MDA) was measured using an MDA assay kit. The level of GPX4 protein was determined by immunofluorescence staining and Western blotting. The protein levels of nuclear-Nrf2 and HO-1 were confirmed using Western blotting. Results: Quercetin improved cell viability, reduced the accumulation of lipid ROS, decreased MDA levels, elevated the protein levels of GPX4 and HO-1, and enhanced nuclear-Nrf2 protein levels in the ferroptosis cell model induced by RSL3. Additionally, the Nrf2 agonist TBHQ reversed ferroptosis in chondrocytes by activating the Nrf2/HO-1 pathway, while the Nrf2 inhibitor ML385 failed to protect against RSL3-induced ferroptosis in chondrocytes. Conclusion: Quercetin suppresses RSL3-induced ferroptosis in chondrocytes by activating the Nrf2/GPX4 signaling pathway, providing a promising therapeutic option for osteoarthritis.