中国复旦大学李晓波团队的研究发现甜菜碱-同型半胱氨酸甲基转移酶通过BACH1-SCD1-油酸轴保护对乙酰氨基酚诱导的急性肝衰竭。相关论文发表在2025年8月5日出版的《中国药理学报》杂志上。

该课题组发现，主要在肝细胞中表达的BHMT在APAP诱导的肝损伤（AILI）小鼠模型中肝脏表达减少，但血清水平升高。GalNAc介导的肝细胞中Bhmt的靶向下调加重了小鼠AILI。通过RNA-seq筛选，该团队发现Bhmt缺乏显著抑制硬脂酰辅酶A去饱和酶1 （SCD1）的表达。Scd1的下调也加重了AILI。从机制上讲，Bhmt敲低降低了转录因子BACH1 （BTB和CNC同源1）的DNA甲基化，导致APAP处理的原代母母肝细胞（PMHs）中BACH1表达上调。然后BACH1结合到Scd1的增强子区，在转录上抑制Scd1。

脂质组学分析显示，Bhmt或Scd1缺乏会降低细胞内不饱和脂肪酸水平，尤其是油酸（OA），而Scd1过表达会增加OA水平，并降低脂质过氧化物。OA给药可减轻AILI，减轻Bhmt或Scd1敲低相关的肝毒性。他们的研究结果表明BHMT通过BACH1-SCD1-OA轴减轻AILI，这表明BHMT可以作为AILI的预防靶点，而增加OA摄入量可能为患者提供饮食益处。

据了解，对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是急性肝衰竭的主要原因，预防或治疗选择有限。甜菜碱-同型半胱氨酸甲基转移酶（BHMT）是蛋氨酸循环中的关键酶，其作用尚不清楚。

附：英文原文

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

Author: Zhang, Yu-ting, Yang, Xiao-ming, Jin, Quan-shan, Chen, Jia-yi, Zhu, Nan-bin, Ju, Yi, Lin, Zi-yan, Zhi, Yang, Dong, Yi-nuo, Li, Chun-min, Mao, Yi-min, Zhi, Xiu-ling, Ma, Ming-yang, Xu, Ya-li, Li, Xiao-bo

Issue&Volume: 2025-08-05

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.

DOI: 10.1038/s41401-025-01622-7

Source: https://www.nature.com/articles/s41401-025-01622-7