Identification of ferroptosis-related genes and potential drugs in osteoarthritis.

Abstract

Background: Osteoarthritis (OA) is a common chronic degenerative joint disease in orthopedics, and ferroptosis is a newly identified mode of cell death present in OA. Inhibition of inflammatory cytokine expression and modulation of chondrocyte ferroptosis related pathways may be novel strategies for the treatment of OA. The purpose of this work was to uncover prospective biomarkers and molecular processes of ferroptosis in OA, as well as to better understand the molecular mechanisms of ferroptosis in OA treated with resveratrol.

Material and methods: We obtained OA gene expression profiles from the Gene Expression Omnibus (GEO) database. OA-expressed ferroptosis-related genes were identified using Genecards data, differential gene analysis, and weighted gene co-expression network analysis. Enrichment analysis was utilized to identify signaling pathways and molecular mechanisms linked with ferroptosis in OA, while immune infiltration analysis indicated immune cell infiltration in OA. The action targets of resveratrol were taken from the TCM database to determine the therapeutic targets of resveratrol for the treatment of OA. To validate the molecular process, molecular docking was performed using the therapeutic targets' enrichment analysis. Finally, in vitro investigations confirmed the molecular mechanism of ferroptosis in resveratrol-treated OA.

Results: Bioinformatic analysis identified 462 OA ferroptosis gene sets, with GPX4, TFRC, SLC7A11, EGFR, and IL1B serving as significant hub genes. Enrichment analysis revealed that ferroptosis was also linked to animal mitophagy, the FoxO signaling pathway, the Toll-like receptor signaling pathway, the PI3K-Akt signaling pathway, inflammation, immune response activation, and cellular autophagy. The immune infiltration data revealed that T_cells_CD4_memory_resting, T_cells_CD4_memory_activated, NK_cells_activated, and Mast_cells_activated were considerably infiltrated in OA. Resveratrol ameliorated OA via modulating autophagy and ferroptosis via GPX4, TFRC, SLC7A11, EGFR, and IL1B, according to a mechanistic study.

Conclusion: We discovered the mechanism of GPX4, TFRC, SLC7A11, and EGFR, IL1B ferroptosis-related genes in OA, and preliminary evidence suggests that resveratrol improves OA by regulating ferroptosis and immunological processes, which may give a new route for OA treatment.