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Betaine-homocysteine methyltransferase protects against acetaminophen-induced acute liver failure via BACH1-SCD1-oleic acid axis

Acta Pharmacologica Sinica volume 47, pages 119–134 (2026)Cite this article

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.

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Fig. 1: BHMT was dramatically downregulated in the mouse livers and primary hepatocytes in response to APAP.
Fig. 2: BHMT protected against APAP-induced hepatotoxicity.
Fig. 3: SCD1, a downstream factor of BHMT, was downregulated in AILI and protected against APAP-induced hepatotoxicity.
Fig. 4: Bhmt deficiency upregulated BACH1 expression through reducing its DNA methylation levels.
Fig. 5: BACH1 transcriptionally repressed Scd1 expression and mediated the suppression of SCD1 induced by BHMT deficiency.
Fig. 6: Bhmt knockdown or Scd1 knockdown reduced levels of intracellular monounsaturated fatty acids (MUFAs).
Fig. 7: OA mitigated the hepatotoxicity aggravated by Scd1 knockdown or Bhmt knockdown in AILI.
Fig. 8: OA protected against APAP-induced hepatotoxicity.

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Data availability

All data supporting the findings of this study are available within the main text, supplementary information, and Source data. The Raw RNA sequencing data were deposited in the CNCB GSA database under the accession number PRJCA033967.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82370597 to XBL, 32171175 to XBL, 82203500 to CML, and 82260120 to XMY), the General Program of Shanghai Natural Science Foundation (25ZR1401075 to XLZ), the Natural Science Foundation of Ningxia (2023AAC03200 to XMY), the Scientific Research Project of Higher Education of Ningxia (NYG2022043 to XMY), and Tianjin Health Research Project (TJWJ2023MS002 to MYM). We thank Dr. Dan Meng from the School of Basic Medical Sciences, Fudan University, for kindly providing the BACH1 antibody (used for ChIP-qPCR), Ad-BACH1, Ad-shBach1, as well as for her insightful discussions about the project.

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  1. These authors contributed equally: Yu-ting Zhang, Xiao-ming Yang, Quan-shan Jin

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Yu-ting Zhang, Quan-shan Jin, Jia-yi Chen, Nan-bin Zhu, Yi Ju, Zi-yan Lin, Xiu-ling Zhi & Xiao-bo Li

  2. NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, China

    Xiao-ming Yang

  3. School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China

    Xiao-ming Yang

  4. Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine; NHC Key Laboratory of Digestive Diseases; Shanghai Research Center of Fatty Liver Disease, Shanghai, 200001, China

    Yang Zhi, Yi-nuo Dong & Yi-min Mao

  5. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China

    Chun-min Li

  6. Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Ming-yang Ma

  7. Department of Pathology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, 250022, China

    Ya-li Xu

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Contributions

YTZ and XBL designed and conducted the experiments; QSJ, JYC, NBZ, YJ, ZYL, YZ, and YND conducted the experiments; CML, XMY, XLZ, MYM, and YLX analyzed and interpreted the data; YTZ, YMM, and XBL wrote the manuscript; YLX and XBL conceptualized and supervised the study. All authors read and approved the final manuscript.

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Correspondence to Ming-yang Ma, Ya-li Xu or Xiao-bo Li.

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Zhang, Yt., Yang, Xm., Jin, Qs. et al. Betaine-homocysteine methyltransferase protects against acetaminophen-induced acute liver failure via BACH1-SCD1-oleic acid axis. Acta Pharmacol Sin 47, 119–134 (2026). https://doi.org/10.1038/s41401-025-01622-7

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