Therapeutic inhibition of HBsAg and HBV cccDNA through a novel phased combination treatment: glycine and interferon-α

作者：Caorui Lin, Ying Huang, Ning Ran, Jie Liu, Linjie Luo, Xin Zhang, Xiaosang Zheng, Zhen Xun, Siyi Xu, Can Liu, Xiaohong Kong, Shiqing Feng, Haiting Mao, Qishui Ou · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-334813 · 被引用次数：7 · 研究领域：Hepatitis B Virus Studies、RNA Interference and Gene Delivery、HIV Research and Treatment

BACKGROUND: The elimination of HBV covalently closed circular DNA (cccDNA) remains a critical hurdle for chronic hepatitis B (CHB) management. OBJECTIVE: In this investigation, we examined the efficacy of glycine administration and its potential enhancement in interferon-α (IFN-α) antiviral efficacy to stimulate hepatocyte proliferation to mitigate cccDNA levels. DESIGN: The study cohort comprised 89 healthy individuals and 496 HBV-infected patients, with subgroups of 30 and 42 participants receiving randomised nucleos(t)ide analogue (NA) and PegIFN-α treatments, respectively. Glycine concentrations were quantified via liquid chromatography‒tandem mass spectrometry, and its diagnostic potential was assessed via receiver operating characteristic curve analysis. The therapeutic impact of glycine was evaluated in various HBV-infected cell lines and murine models via various methodologies including transcriptomic sequencing, metabolomics sequencing, flow cytometry, immunofluorescence and in situ hybridisation. RESULTS: Elevated serum glycine levels with a robust positive correlation with serum alanine aminotransferase levels (R=0.7650) were observed in HBV-infected patients relative to healthy controls. The area under the curve for differentiating patients with HBeAg-expressing CHB from healthy controls was 0.9701. Glycine supplementation diminished HBV cccDNA levels by approximately 50% by promoting hepatocyte proliferation. Glycine is metabolised into a one-carbon unit, activat...