Lactylation-Driven YTHDC1 Alleviates MASLD by Suppressing PTPN22-Mediated Dephosphorylation of NLRP3

  • Adv Sci (Weinh). 2025 Nov 26:e10192. doi: 10.1002/advs.202510192.
Feng Zhang  1  2 ,  Linghua Zeng  2 ,  Kunkun Zou  2 ,  Keying Lin  2 ,  Fangting Yao  2 ,  Jinglun Song  2 ,  Shumeng Zhang  2 ,  Hanshu Feng  2 ,  Zhichao Yang  3 ,  Chunlei Wang  2 ,  Hongtao Diao  2 ,  Xue Kong  2 ,  Tengfei Pan  2 ,  Joonki Kim  4 ,  Tianqi Duo  2  5 ,  Linqiang Li  3 ,  Yu Bian  1  2  5
Affiliations
  • 1. General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China.
  • 2. Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 3. Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.
  • 4. Natural Product Applied Science, KIST School, University of Science & Technology (UST), Gangneung, 25451, Republic of Korea.
  • 5. The Academician Cooperative Laboratory of Basic and Translational Research on Chronic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.
PMID: 41298230 DOI: 10.1002/advs.202510192
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is among the most prevalent chronic liver diseases worldwide. The expression of YTH domain-containing protein 1 (YTHDC1) is significantly reduced in patients and mouse models with MASLD. Hepatocyte-specific knockout of YTHDC1 exacerbates HFD-induced hepatic lipid accumulation. Lactate accumulation and enhanced arginyl-tRNA synthetase 1 (AARS1)-mediated K565-specific lactylation are shown to drive the ubiquitination-mediated degradation of YTHDC1. This work proposes that under MASLD conditions, diminished YTHDC1-LDHA binding elevates free LDHA levels, which enhances YTHDC1 lactylation and suppresses its expression. This creates a positive feedback loop that exacerbates the progression of MASLD. Mechanistically, protein tyrosine Phosphatase nonreceptor type 22 (PTPN22), identified as a downstream target of YTHDC1, exacerbates hepatic inflammation and lipid accumulation by dephosphorylating and activating NLRP3 at tyrosine 861, which in turn promotes the release of IL-1β and IL-18. Furthermore, mebendazole, a small-molecule drug targeting YTHDC1, significantly alleviates MASLD. In conclusion, YTHDC1 mitigates MASLD by inhibiting the PTPN22-mediated dephosphorylation and activation of NLRP3, offering new insights into therapeutic strategies for MASLD.

Keywords
MASLD; NLRP3; PTPN22; YTHDC1; lactylation.
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