210-OR: RNA Binding Protein YTHDC1 Critically Regulates Liver Metabolism and Homeostasis

Introduction and Objective: RNA N6-methyladenosine (m6A) modification emerges to pivotally regulate cell proliferation, differentiation, and functions. The METTL3/METTL14 complex installs m6A on mRNA (m6A writer). YTH family members (e.g. YTHDC1) bind to m6A-marked RNA (m6A readers) and control RNA fate, proteostasis, and cell functions. We aimed to delineate the role of hepatic YTHDC1 in metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Hepatocyte-specific Ythdc1 knockout mice were generated by transducing Ythdc1f/f mice with AAV8-TBG-Cre vector via tail veins. To reconstitute livers with YTHDC1 or YTHDC1W377A (unable to bind to m6A), Ythdc1f/f mice were cotransduced with AAV8-TBG-Cre and AAV8-TBG-Flag-YTHDC1 or AAV8-TBG-Flag-YTHDC1W377A vectors. Liver integrity and triacylglycerol (TAG) levels are assessed using chemical and immunobiological assays. Results: Mice with hepatocyte-specific deletion of Ythdc1, both males and females on normal chow diet, developed severe MASLD with massive liver steatosis, injury, inflammation, and fibrosis. Hepatocyte-specific reconstitution with YTHDC1, but not m6A binding-defective YTHDC1W377A, fully rescued MASLD. At the molecular level, YTHDC1 directly targeted CD36 (fatty acid transporter) and PPARα genes, thereby suppressing hepatic lipid uptake while stimulating fatty acid β oxidation. Hepatocyte-specific restoration of CD36 and PPARα largely reversed MASLD phenotypes in Ythdc1 knockout mice. Liver YTHDC1 was markedly downregulated in mice and patients with MASLD, likely contributing to disease progression. Conclusion: We have identified hepatic YTHDC1 as a pivotal m6A reader to control hepatic liver uptake and β oxidation. Downregulation of hepatic YTHDC1 or aberrant m6A pathways play a critical role in MASLD pathogenesis and serve as potential therapeutic targets for MASLD treatment. Disclosure Q. Zheng: None. L. Baron: None. S. Zhou: None. L. Rui: None. Funding American Diabetes Association (1-25-PDF-37); American Heart Association (831585)