Sat1/Hif-1Α Regulates Macrophage Ferroptosis Promoting Temporomandibular Joint Osteoarthritis

Synovial macrophage inflammation is a critical contributor to temporomandibular joint osteoarthritis (TMJOA) progression. Ferroptosis, an iron-dependent form of inflammatory cell death, has emerged as a key player in inflammatory disorders. This study aims to discuss basic mechanisms of ferroptosis and SAT1/HIF-1α regulation in macrophage inflammation. We constructed a complete Freund's adjuvant (CFA) induced TMJOA rat model, followed by synovial tissue RNA extraction and transcriptome profiling. Differentially expressed genes (DEGs) were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). Ferroptosis was validated through quantification of Fe²⁺/Fe³⁺, peroxides, and immunofluorescence. RNA interference (RNAi)-mediated SAT1 silencing was performed in mouse bone marrow-derived macrophages (BMMs). RNA-seq of SAT1-silenced BMMs, alongside RT-qPCR, western blotting, co-immunoprecipitation (Co-IP), and fluorescence were tested in RAW264.7 and SAT1-silenced BMMs. The KEGG and GSEA enrichment analyses indicated the ferroptosis related genes play an important role in TMJOA meanwhile Fe2+/Fe3+ concentration, MDA, lipid peroxides increased in the tissue (p<0.05). Expression of SAT1 in TMJOA increased significantly found in rat mRNA chip and human GEO database (GSE205389), was confirmed by immunofluorescence. RNA-seq conducting on SAT1 silenced mouse BMMs showed SAT1 silence leads to increasing expression of antioxidant genes like SLC7A11 and decreasing of HIF-1α(p<0.05 or 0.01). Our results demonstrated that ferroptosis participates in macrophage inflammation and is regulated by SAT1. SAT1 silencing reduced inflammation and ferroptosis by inducing HIF-1α.