Diosgenin ameliorates colitis by inhibiting mitochondrial DNA synthesis in macrophages via STAT2-CMPK2 pathway

  • Phytomedicine. 2025 Nov 25:150:157605. doi: 10.1016/j.phymed.2025.157605.
Xin Qiao  1 ,  Lei Zhang  2 ,  Ting Wang  3 ,  Xinyi Liang  2 ,  Shenmeng Yao  2 ,  Lei Wang  4 ,  Gaoxiang Ma  5 ,  Jie Yang  6 ,  Xiaodong Wen  7
Affiliations
  • 1. Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, China Pharmaceutical University, Nanjing, China; School of Pharmacy, Shanxi Medical University, Taiyuan, China.
  • 2. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 3. Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
  • 4. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 5. Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 6. Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
  • 7. Pukou Hospital of Chinese Medicine affiliated to China Pharmaceutical University, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
PMID: 41351988 DOI: 10.1016/j.phymed.2025.157605
Abstract

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence, posing ongoing therapeutic challenges. Diosgenin (DSG), a natural steroidal saponin, exhibits anti-inflammatory properties. However, its molecular mechanisms in UC are poorly understood.

Purpose: This study sought to clarify the molecular mechanisms and therapeutic targets responsible for DSG's protective effects against UC.

Methods: A murine colitis model induced by dextran sulfate sodium was used to assess DSG efficacy. Mechanistic insights were obtained from RNA Sequencing analysis and confirmed in RAW264.7 and bone marrow-derived macrophages through Stat2 knockdown/overexpression experiments. Chromatin immunoprecipitation and surface plasmon resonance assays were used to investigate DSG-STAT2 interactions.

Results: DSG markedly alleviated colonic inflammation and tissue damage in DSS-treated mice. It significantly modulated macrophage polarization in colonic lamina propria lymphocytes. RNA-seq and Western blotting revealed that DSG selectively suppressed STAT2 phosphorylation and CMPK2 expression in macrophages, while attenuated LPS-induced mitochondrial DNA (mtDNA) synthesis and mitochondrial ROS (mtROS) production. STAT2 directly bound to the Cmpk2 promoter, and Stat2 silencing abolished LPS-driven Cmpk2 transcription and mtDNA synthesis. DSG interacted with STAT2 at Pro630 and Lys689 residues, and its inhibitory effects on CMPK2 and mtDNA were reversed by STAT2 overexpression.

Conclusions: DSG exerts its anti-colitis effects by selectively targeting STAT2 at Pro630 and Lys689, thereby suppressing CMPK2-mediated mtDNA overproduction. The discovery of a STAT2-dependent mechanism in DSG presents a potential therapeutic approach for UC.

Keywords
CMPK2; Colitis; Diosgenin; STAT2; mtDNA.
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