1,25(OH)2D3 ameliorates DSS-induced intestinal ferroptosis through the SIRT3-SOD2-mtROS pathway.

Ferroptosis has been shown to play a significant role in the pathogenesis of ulcerative colitis (UC). This study investigated the effects of 1,25(OH)2D3 supplementation on ferroptosis in dextran sulfate sodium (DSS)-evoked colitis. Intestinal VDR was reduced in UC patients. Accordingly, GPX4 was downregulated and ACSL4 was upregulated in the intestine of UC patients. Animal experiments indicated that vitamin D deficiency exacerbated DSS-induced intestinal ferroptosis in mice. Conversely, pretreatment with 1,25(OH)2D3 alleviated DSS-induced ferroptosis in mouse intestine. Similarly, 1,25(OH)2D3 supplementation inhibited DSS-induced ferroptosis in HT-29 cells. Furthermore, we found decreased intestinal SIRT3 protein and increased acetylated superoxide dismutase 2 (Ac-SOD2) in UC patients. Pretreatment with 1,25(OH)2D3 attenuated DSS-induced downregulation of SIRT3 and acetylation of SOD2 in both mouse intestine and HT-29 cells. Moreover, 1,25(OH)2D3 pretreatment inhibited mitochondrial reactive oxygen species (mtROS) in DSS-treated HT-29 cells. Finally, transfection with SIRT3 siRNA antagonized the protective effect of 1,25(OH)2D3 on ferroptosis in DSS-treated HT-29 cells. Overall, our results suggest that 1,25(OH)2D3 alleviates DSS-induced intestinal ferroptosis via the SIRT3-SOD2-mtROS pathway, further supporting the potential use of 1,25(OH)2D3 supplementation in UC treatment.