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

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.