Silymarin attenuates cardiac injury and inflammation in adjuvant-induced rheumatoid arthritis rats through activation of the Nrf2/SLC7A11/GPX4 signaling pathway.

OBJECTIVE: To investigate the protective effects of silymarin (SIL) against adjuvant-induced cardiac injury and inflammation in rats with rheumatoid arthritis (RA) and to elucidate the underlying mechanisms through in vivo and in vitro experiments. METHODS: RA was induced in rats using Freund's complete adjuvant (FCA), which also causes cardiac injury as an extra-articular manifestation of RA. Rats were treated with different doses of SIL to evaluate its cardioprotective effects. Myocardial injury and inflammatory responses were assessed in vivo, while cardiac cells with Nuclear factor erythroid-2-related factor 2 (Nrf2) silencing by small interfering RNA (siRNA) were used in vitro to clarify the role of the Nrf2/solute carrier family 7 member 11/Glutathione peroxidase 4 (Nrf2/SLC7A11/GPX4) pathway. Inflammatory cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA); myocardial cell viability and proliferation were evaluated by Cell Counting Kit-8 (CCK-8), clonogenic, and 5-Ethynyl-2'-deoxyuridine (EdU) assays; apoptosis was analyzed by flow cytometry; and the expression of Nrf2, SLC7A11, GPX4, and apoptosis-related proteins was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Histopathologic changes were examined by hematoxylin and eosin (H&E) staining. RESULTS: SIL treatment effectively alleviated myocardial cell injury in SiNrf2-induced cardiac cells and significantly reduced the secretion of inflammatory factors interleukin-1 beta (IL-1β), IL-6, IL-17, and tumor necrosis factor-alpha (TNF-α). Furthermore, SIL activated the Nrf2/SLC7A11/GPX4 signaling pathway, improved myocardial tissue morphology, and suppressed apoptosis in RA rats. CONCLUSION: SIL exerts protective effects against RA-associated cardiac injury and inflammation, primarily through activation of the Nrf2/SLC7A11/GPX4 signaling pathway. These findings provide mechanistic insight and experimental evidence supporting the use of SIL as a therapeutic agent for preventing cardiac complications in RA.