The protective role of TRIM16 in rheumatoid arthritis: mechanisms of modulating ferroptosis

Abstract

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe²⁺ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.