2. Academic Validation
  3. Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle

Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle

  • Nat Commun. 2025 Aug 26;16(1):7961. doi: 10.1038/s41467-025-62731-9.
Shanshan Liu # 1 2 3,  Yu Ji # 1 2 3,  Luyang Wei # 1 2 3,  Yiqiao Zhang 1 2 3,  Linghang Zeng 4,  Yiyang Min 1 2 3,  Danyang Yin 5,  Kun Liu 1,  Chengjian Guan 6 7 8,  Shumeng Liu 9,  Huajing Yu 10 11 12,  Zhongtao Zhang 13 14 15
Affiliations

Affiliations

  • 1 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 2 State Key Lab of Digestive Health, Beijing, China.
  • 3 National Clinical Research Center for Digestive Diseases, Beijing, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 5 Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 6 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. guanchengjian@mail.ccmu.edu.cn.
  • 7 State Key Lab of Digestive Health, Beijing, China. guanchengjian@mail.ccmu.edu.cn.
  • 8 National Clinical Research Center for Digestive Diseases, Beijing, China. guanchengjian@mail.ccmu.edu.cn.
  • 9 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. shumengliu@ccmu.edu.cn.
  • 10 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. huajingyu@pku.edu.cn.
  • 11 State Key Lab of Digestive Health, Beijing, China. huajingyu@pku.edu.cn.
  • 12 National Clinical Research Center for Digestive Diseases, Beijing, China. huajingyu@pku.edu.cn.
  • 13 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. zhangzht@ccmu.edu.cn.
  • 14 State Key Lab of Digestive Health, Beijing, China. zhangzht@ccmu.edu.cn.
  • 15 National Clinical Research Center for Digestive Diseases, Beijing, China. zhangzht@ccmu.edu.cn.
  • # Contributed equally.
PMID: 40858572 DOI: 10.1038/s41467-025-62731-9
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), potentially ameliorated by bariatric-metabolic surgery, remains a global health concern in the absence of approved drugs. Protein post-translational modifications (PTMs) are crucial for MASLD. However, the functional significance of lysine crotonylation (Kcr) remains unclear. We aimed to investigate the mechanisms by Kcr-regulated IDH1 in the tricarboxylic acid (TCA) cycle and MASLD development. Herein, we reported a quantitative proteomics analysis of global crotonylome upon MASLD and Post-bariatric. Specifically, decreases in K58cr, K151cr, K212cr and K345cr of IDH1 upon MASLD were observed. PCAF and SIRT7 dynamically regulated the IDH1 Kcr. Abolishment of IDH1 Kcr impaired TCA cycle by decreasing IDH1 enzymatic activity. Male mice with liver-specific expression of crotonylation-mimic mutants of IDH1 were resistant to HFD-induced obesity, Insulin resistance, glucose intolerance and MASLD. Our findings unravel the mechanisms of IDH1 Kcr and indicate that targeting PCAF/SIRT7-IDH1 Kcr and metabolites may be a promising strategy for MASLD therapy.

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