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

  • J Adv Res. 2026 Apr 22:S2090-1232(26)00355-3. doi: 10.1016/j.jare.2026.04.049.
Yihang Gong  1 ,  Jiandi Chen  2 ,  Feng Zhang  3 ,  Ruoqi Huang  4 ,  Lei Mai  5 ,  Yuchun Xu  5 ,  Wang Zhao  5 ,  Xiaohong Wei  6 ,  Jun Zheng  7 ,  Xianzhi Liu  8 ,  Jianxu Chen  9
Affiliations
  • 1. Department of Gastroenterology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China; Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Institute, Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou 510000, China.
  • 2. Department of Radiology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China.
  • 3. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Institute, Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou 510000, China.
  • 4. Department of Neurosurgery, the Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou 510000, China.
  • 5. Department of Gastroenterology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China.
  • 6. Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China.
  • 7. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Institute, Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou 510000, China. Electronic address: [email protected].
  • 8. Department of Gastroenterology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, Fujian, China. Electronic address: [email protected].
  • 9. Department of Gastroenterology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China. Electronic address: [email protected].
PMID: 42031105 DOI: 10.1016/j.jare.2026.04.049
Abstract

Background and aims: 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.

Approach and results: 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.

Conclusions: Our research identifies that TAF1C drives liver steatosis through epigenetic reprogramming, positioning it as a therapeutic target for MASLD.

Keywords
CRISPR screening; Histone modification; Lipid metabolism; Metabolic dysfunction-associated steatotic liver disease; TAF1C.
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