Liu Wenli, Hu Kaiheng, Fu Yaqing, Zhou Tianmin, Zhong Qingmei, Wang Wu, Gui Yang, Zhang Ping, Yao Di, Yang Xiaohong, Zhu Weifeng, Liu Zhuoqi, Luo Daya, Xiao Yingqun
Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China.
Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
Sci Rep. 2025 Mar 18;15(1):9250. doi: 10.1038/s41598-025-93650-w.
Given the resistance to conventional treatments and limitations of immune checkpoint blockade therapy in hepatocellular carcinoma (HCC), it is imperative to explore novel prognostic models and biomarkers. The dependence of cancer cell on exogenous methionine, known as Hoffman effect, is a hallmark of HCC, with numerous studies reporting a strong correlation between methionine metabolism and tumor development. Betaine-homocysteine S-methyltransferase (BHMT), a critical component of methionine metabolism pathway, has polymorphisms linking to poor prognosis in multiple cancers. Nevertheless, there is little literature regarding the relationship between methionine metabolism and incidence, mortality of HCC, as well as the function of BHMT in HCC progression. In this study, by analyzing multiple datasets, we constructed a methionine metabolism-related prognostic model and thoroughly investigated the influence of BHMT on the prognosis of HCC. Bioinformatics analysis revealed a marked decrease in BHMT expression in HCC, which was linked to adverse clinical outcomes. CIBERSORT results suggest that BHMT promotes infiltration of M1 macrophages. Our results suggest its potential as an ideal prognostic biomarker for anti PD-L1 immunotherapy. In summary, this study innovatively provides first methionine metabolism-related prognostic model and unveils the tumor suppressive function of BHMT in HCC, providing potential mechanism by which BHMT exert its function.
鉴于肝细胞癌（HCC）对传统治疗的耐药性以及免疫检查点阻断疗法的局限性，探索新的预后模型和生物标志物势在必行。癌细胞对外源性甲硫氨酸的依赖性，即霍夫曼效应，是HCC的一个标志，大量研究报告了甲硫氨酸代谢与肿瘤发展之间的密切相关性。甜菜碱-同型半胱氨酸S-甲基转移酶（BHMT）是甲硫氨酸代谢途径的关键组成部分，其多态性与多种癌症的不良预后相关。然而，关于甲硫氨酸代谢与HCC的发病率、死亡率之间的关系，以及BHMT在HCC进展中的作用，相关文献较少。在本研究中，通过分析多个数据集，我们构建了一个与甲硫氨酸代谢相关的预后模型，并深入研究了BHMT对HCC预后的影响。生物信息学分析显示，HCC中BHMT表达显著降低，这与不良临床结果相关。CIBERSORT结果表明，BHMT促进M1巨噬细胞浸润。我们的结果表明其作为抗PD-L1免疫治疗理想预后生物标志物的潜力。总之，本研究创新性地提供了首个与甲硫氨酸代谢相关的预后模型，并揭示了BHMT在HCC中的肿瘤抑制功能，为BHMT发挥其功能提供了潜在机制。
