Halting hepatocellular carcinoma: Identifying intercellular crosstalk in HBV-driven disease.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-04-22 Epub Date: 2025-03-30 DOI:10.1016/j.celrep.2025.115457

Lingyun Zhou, Chang-Hai Liu, Duoduo Lv, Klarke Michael Sample, Ángela Rojas, Yugu Zhang, Huandi Qiu, Linye He, Li Zheng, Liyu Chen, Binru Cai, Yiguo Hu, Manuel Romero-Gómez

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Abstract

Hepatitis B infection can lead to liver fibrosis and hepatocellular carcinoma (HCC). Despite antiviral therapies, some patients still develop HCC. This study investigates hepatitis B virus (HBV)-induced hepatocyte-hepatic stellate cell (HSC) crosstalk and its role in liver fibrosis and HCC. Using MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models, this study reveals that HBV transcription affected hepatocyte development, activated the DNA repair pathway, and promoted glycolysis. HBV activated nicotinamide phosphoribosyltransferase (NAMPT) through DNA damage receptor ATR. NAMPT-insulin receptor (INSR)-mediated hepatocyte-HSC crosstalk caused HSCs to develop a myofibroblast phenotype and activated telomere maintenance mechanisms via PARP1 multisite lactylation. Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC progression. Targeting this pathway could be a promising strategy for chronic HBV infection management.

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阻止肝细胞癌：识别hbv驱动疾病中的细胞间串扰。

乙型肝炎感染可导致肝纤维化和肝细胞癌。尽管有抗病毒治疗，一些患者仍然会发生HCC。本研究探讨乙型肝炎病毒（HBV）诱导的肝细胞-肝星状细胞（HSC）串扰及其在肝纤维化和HCC中的作用。通过myc驱动的肝癌干细胞类器官、hcc患者来源的异种移植（PDX）模型和HBV复制模型，本研究发现HBV转录影响肝细胞发育，激活DNA修复途径，促进糖酵解。HBV通过DNA损伤受体ATR激活烟酰胺磷酸核糖基转移酶（NAMPT）。nampt -胰岛素受体（INSR）介导的肝细胞- hsc串话通过PARP1多点乳酸化导致hsc发展成肌成纤维细胞表型并激活端粒维持机制。抑制ATR-NAMPT-INSR-PARP1通路可有效阻断hbv诱导的肝纤维化和HCC进展。靶向这一途径可能是一种有希望的慢性HBV感染管理策略。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.