The role of HIF signal mediated autophagy dysfunction in synovial fibroblasts in rheumatoid arthritis and the targeted regulation of kaempferol.

Background: Rheumatoid arthritis (RA) is an autoimmune condition that causes joint damage and persistent synovial inflammation. Recent research has demonstrated the critical roles that fibroblastic synoviocytes (FLS) autophagy abnormalities, hypoxia inducible factor (HIF) signaling activation, and aberrant production of inflammatory factors play in the pathophysiology of RA. Although kaempferol is a naturally occurring flavonoid with anti-inflammatory, antioxidant, and other biological properties, it is yet unknown how it controls FLS autophagy in RA.

Methods: To screen for autophagy-associated core genes, this study used transcriptome data related to RA in conjunction with weighted gene co-expression network analysis (WGCNA) and LASSO regression. The function of immune cells in RA lesions was investigated in conjunction with immune infiltration research, and in vitro cell tests confirmed kaempferol's regulatory effect on important genes.

Results: Through screening, 8 key genes that are intimately linked to RA autophagy were found. In addition to IL-17 signaling and aberrant mitochondrial autophagy, it was discovered that the HIF signaling pathway was highly activated in RA synovial cells, which promoted inflammatory responses and aberrant cell proliferation. Significant neutrophil and macrophage aggregation was revealed by immune infiltration studies, aggravating inflammation and hypoxia in synovial tissue. Kaempferol controlled the expression of key genes such HIF1A, MYC, and HMOX1, enhanced mitochondrial activity, and dramatically reduced the proliferation of FLS, according to cell tests.

Conclusion: This study reveals the molecular mechanism of autophagy imbalance in FLS in RA, emphasizes the synergistic effect of HIF-IL17 mitochondrial autophagy pathway, and clarifies the potential of kaempferol to exert therapeutic effects by regulating this pathway, providing new ideas for targeted therapy of RA.