1,25(OH)2D3 Ameliorates DSS-induced Intestinal Ferroptosis through the SIRT3-SOD2-mtROS Pathway

Hong-Qian Wang; Ya-Wen Zhu; Zi-Yue Dou; Zhuo Chen; Cheng-Cheng Tong; Xue He; Xiao-Han Ma; Jing Guan; De-Xiang Xu; Xi Chen

doi:10.1016/j.jnutbio.2025.109999

1,25(OH)₂D₃ Ameliorates DSS-induced Intestinal Ferroptosis through the SIRT3-SOD2-mtROS Pathway

J Nutr Biochem. 2025 Jun 11:109999. doi: 10.1016/j.jnutbio.2025.109999. Online ahead of print.

Authors

Affiliations

¹ Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Provincial Key Laboratory of Digestive Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, China.
² Department of Toxicology, Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China. Electronic address: xudex@126.com.
³ Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Provincial Key Laboratory of Digestive Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: ayfychenxi@163.com.

PMID: 40513839
DOI: 10.1016/j.jnutbio.2025.109999

Abstract

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.

Keywords: Colitis; Ferroptosis; SIRT3; VDR; Vitamin D.