KDM6B promotes ferroptosis in rheumatoid arthritis fibroblast-like synoviocytes via the miR-128-3p/SLC7A11 axis through H3K27me3 modification.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, primarily driven by fibroblast-like synoviocytes (FLSs) that trigger synovial inflammation and joint destruction. This study explores the mechanisms of KDM6B in ferroptosis in RA-FLSs, providing a theoretical basis for the treatment of RA.

Methods: RA-FLSs were isolated from RA synovial tissue samples. si-KDM6B was transfected into RA-FLSs, followed by the detection of KDM6B and miR-128-3p using qRT-PCR and Western blot. Cell viability was assessed using the CCK-8 assay. The levels of ROS, GSH, MDA, and Fe²⁺ were evaluated, and the expression of GPX4, SLC7A11, and ACSL4 was measured. The enrichment of KDM6B and H3K27me3 on the miR-128-3p promoter was detected by ChIP. The binding relationship between miR-128-3p and SLC7A11 was validated by dual-luciferase reporter assay. Combined experiments were designed to validate the mechanism.

Results: KDM6B was highly expressed in RA tissues and RA-FLSs. Inhibition of KDM6B increased cell viability, elevated ROS, MDA, and Fe²⁺, decreased GSH, reduced GPX4 and SLC7A11, and increased ACSL4. KDM6B and H3K27me3 were enriched on the miR-128-3p promoter. Inhibition of KDM6B increased H3K27me3 enrichment and suppressed miR-128-3p expression. miR-128-3p targeted and inhibited SLC7A11 expression. miR-128-3p overexpression or SLC7A11 inhibition partially reversed the inhibitory effect of KDM6B inhibition on ferroptosis in RA-FLSs.

Conclusion: KDM6B promotes ferroptosis in RA-FLSs via the miR-128-3p/SLC7A11 axis through the removal of histone H3K27me3 modification.