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

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.