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

  • J Nutr Biochem. 2025 Jul 9:144:109999. doi: 10.1016/j.jnutbio.2025.109999.
Hong-Qian Wang  1 ,  Ya-Wen Zhu  1 ,  Zi-Yue Dou  1 ,  Zhuo Chen  1 ,  Cheng-Cheng Tong  1 ,  Xue He  1 ,  Xiao-Han Ma  1 ,  Jing Guan  1 ,  De-Xiang Xu  2 ,  Xi Chen  3
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: [email protected].
  • 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: [email protected].
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.
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