Context-dependent protective and pathogenic functions of YTHDF1 in MASLD and hepatocellular carcinoma: Mechanisms and design of therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease and can progressively develop into inflammatory metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. During this progression, activation of hepatic stellate cells (HSCs) leads to excessive accumulation of extracellular matrix. There is a growing trend to develop into hepatocellular carcinoma (HCC). The limited availability of effective therapeutics highlights the need to better understand the underlying pathogenic mechanisms. N6-methyladenosine (m6A) is a key post-transcriptional RNA modification that regulates gene expression and governs a broad range of physiological and pathological processes. YTH domain family 1 (YTHDF1) is a reader protein that recognizes m6A modifications on mRNAs and enhances their stability or translation by interacting with key components of the translation machinery. YTHDF1 exhibits context-dependent functions in MASLD and liver fibrosis, while it promotes HCC pathogenesis. Hepatocytic YTHDF1 alleviates MASLD by improving mitochondrial function, serving as a protective factor during its early stages. YTHDF1 in HSCs is important for initiating liver fibrosis, yet it also plays a crucial role in regulating HSC ferroptosis to counteract established fibrosis. Our structure-based analyses of YTHDF1 inhibitors reveal novel concepts, including inhibition of YTHDF1-induced condensates and direct degradation of YTHDF1 proteins by fullerene derivatives and metal-organic frameworks. YTHDF1 inhibitors serve as selective chemical probes for interrogating YTHDF1's cell type-specific functions in MASLD. They are also promising candidates for in vivo evaluation to treat MASLD and HCC and to prevent liver fibrosis at early stages.