Genome-wide CRISPR screen identifies TAF1C as an epigenetic determinant of lipid deposition via ACSL4-dependent ferroptosis in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent liver disease, garnering considerable attention. Currently, there are no satisfactory drugs available clinically due to the lack of efficacious therapeutic targets. By using genome-wide CRISPR/Cas9 screening and ATAC-seq in steatotic hepatocytes, we systematically identify TAF1C as crucial epigenetic determinant of MASLD. CeMMEC13, an inhibitor of TAF1, significantly alleviates hepatic steatosis. Knockdown of TAF1C, significantly ameliorates lipid accumulation in steatotic hepatocytes both in vitro and in vivo. TAF1C expression was gradually upregulated in liver tissues during MASLD progression. Overexpressing TAF1C induces excessive lipid deposition in steatotic hepatocytes. Mechanistically, TAF1C directly interacts with the H3K4 methyltransferase SETD1A to reprogram epigenetic landscape by administrating H3K4me3 and H3K27me3 marks. TAF1C regulates H3K27ac deposition, thereby modulating the activities of enhancers and super-enhancers, which ultimately upregulates the expression of genes associated with lipid metabolism. By epigenetic reprogramming, TAF1C increases ACSL4 expression, accelerating lipid synthesis and inducing ferroptosis. Our research identifies that TAF1C drives liver steatosis through epigenetic reprogramming, positioning it as a therapeutic target for MASLD.