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Lactylation-Driven YTHDC1 Alleviates MASLD by Suppressing PTPN22-Mediated Dephosphorylation of NLRP3
Feng Zhang1,2, Linghua Zeng2, Kunkun Zou2
1General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China.
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.
Insights
Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is worsened by reduced YTHDC1. This study reveals YTHDC1 inhibits inflammation and lipid buildup, offering new therapeutic targets for MASLD.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread liver condition.
- YTH domain-containing protein 1 (YTHDC1) expression is decreased in MASLD.
- YTHDC1 deficiency in hepatocytes worsens diet-induced liver fat accumulation.
Purpose of the Study:
- To investigate the role of YTHDC1 in MASLD pathogenesis.
- To elucidate the molecular mechanisms underlying YTHDC1 regulation in MASLD.
- To explore potential therapeutic strategies targeting YTHDC1 for MASLD.
Main Methods:
- Analysis of YTHDC1 expression in MASLD patients and mouse models.
- Investigating the impact of hepatocyte-specific YTHDC1 knockout on high-fat diet (HFD)-induced liver steatosis.
- Identifying proteins involved in YTHDC1 degradation, including AARS1 and its lactylation activity.
- Examining the interaction between YTHDC1 and LDHA.
- Identifying downstream targets of YTHDC1, such as PTPN22 and its effect on NLRP3 inflammasome activation.
- Evaluating the therapeutic potential of mebendazole, a YTHDC1-targeting drug, in MASLD models.
Main Results:
- YTHDC1 expression is significantly reduced in MASLD.
- Lactate accumulation and AARS1-mediated lactylation drive YTHDC1 degradation.
- A positive feedback loop involving YTHDC1, LDHA, and lactylation exacerbates MASLD.
- YTHDC1 inhibits PTPN22, which normally activates NLRP3, thereby reducing hepatic inflammation and lipid accumulation.
- Mebendazole treatment alleviates MASLD by modulating YTHDC1 activity.
Conclusions:
- YTHDC1 plays a protective role in MASLD by suppressing the PTPN22-NLRP3 inflammatory axis.
- YTHDC1 degradation via lactylation is a key mechanism in MASLD progression.
- Targeting YTHDC1 with drugs like mebendazole shows promise for MASLD treatment.
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