@article{APS11430,
author = {Yu-ting Zhang and Xiao-ming Yang and Quan-shan Jin and Jia-yi Chen and Nan-bin Zhu and Yi Ju and Zi-yan Lin and Yang Zhi and Yi-nuo Dong and Chun-min Li and Yi-min Mao and Xiu-ling Zhi and Ming-yang Ma and Ya-li Xu and Xiao-bo Li},
title = {Betaine-homocysteine methyltransferase protects against acetaminophen-induced acute liver failure via BACH1-SCD1-oleic acid axis},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {1},
year = {2025},
keywords = {},
abstract = {Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure, with limited preventive or therapeutic options. The role of betaine-homocysteine methyltransferase (BHMT), a key enzyme in the methionine cycle, remains unclear. We found that BHMT, primarily expressed in hepatocytes, showed reduced expression in the liver but elevated serum levels in the APAP-induced liver injury (AILI) mouse model. GalNAc-mediated targeted knockdown of Bhmt in hepatocytes aggravated AILI in mice. Through RNA-seq screening, we found that Bhmt deficiency dramatically suppressed stearoyl-coenzyme A desaturase 1 (SCD1) expression. Knockdown of Scd1 also exacerbated AILI. Mechanistically, Bhmt knockdown decreased the DNA methylation of BACH1 (BTB and CNC homology 1), a transcriptional factor, leading to upregulated BACH1 expression in primary mouse hepatocytes (PMHs) treated with APAP. BACH1 then bound to the enhancer region of Scd1, transcriptionally repressing SCD1. Lipidomic analysis revealed that Bhmt or Scd1 deficiency reduced levels of intracellular unsaturated fatty acids, particularly oleic acid (OA), whereas SCD1 overexpression increased OA levels and decreased lipid peroxides. OA administration alleviated AILI and mitigated the hepatotoxicity associated with Bhmt or Scd1 knockdown. Our findings indicate that BHMT mitigates AILI via the BACH1-SCD1-OA axis, suggesting that BHMT could serve as a preventive target for AILI, while increasing OA intake may offer dietary benefits for patients.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11430}
}