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. 2025 Aug;68(8):2456-2471.
doi: 10.1007/s11427-024-2793-x. Epub 2025 May 30.

N6-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

Yaxu Liang #  1 , Weiwei Yu #  2 , Haifeng Sun #  3 , Dayu Wang  1 , Zhibo Wang  1 , Hailing Shi  4   5   6 , Yang Cao  4 , Zijie Zhang  4   7 , Jun Liu  4   8 , Zhongyu Zou  4 , Jiangbo Wei  4 , Tong Wu  4 , Dongming Yu  1 , Jun Qi  1 , Jiamin Wu  1 , Bryan C Dickinson  4 , Pingping Zhu  9 , Bin Shen  10 , Beicheng Sun  11 , Chuan He  4   5   6 , Xiang Zhong  12   13
Affiliations

N6-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

Yaxu Liang et al. Sci China Life Sci. 2025 Aug.

Abstract

Liver injury is a major health issue with significant implications for liver function and overall well-being, but precise mechanisms of the N6-methyladenine (m6A) reader YTHDF3 in liver injury remain severely understudied. Here, we discovered that Ythdf3 knockout exacerbated CCL4-induced liver injury with a reduction in functional hepatocytes and liver stem cells using single cell RNA-sequencing and organoid culture. Furthermore, Mettl14 and YTHDF3-dependent RNA m6A dysregulation induced DNA damage. Moreover, we found YTHDF3 could bind and modulate CCAAT/enhancer-binding protein-alpha (CEBPA) translation in an m6A-dependent manner. Mechanistically, knockout of Ythdf3 impeded the translation of CEBPA, subsequently inhibiting the expression of poly(ADP-ribose) (PAR) polymerase-1 (PARP1) and Peroxiredoxin 2 (PRDX2). This inhibition promoted DNA damage and genomic instability, ultimately exacerbating liver damage. This work uncovers an essential role of m6A/YTHDF3/CEBPA regulatory axes in governing cell fates and genomic stability, thereby preventing liver injury. Importantly, these findings offer potential therapeutic avenues for targeting YTHDF3 and CEBPA in the treatment of liver injury-related diseases.

Keywords: CEBPA; YTHDF3; genome stability; liver injury; stem cell.

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Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest. The procedures involving mice experiments were conducted in accordance with guidelines set by the Animal Ethics Committee of Nanjing Agricultural University (Permit number SYXK-2017-0007).

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