Multiomics Analyses\nReveal that Fatty Acid Metabolism\nand TCA Cycle Contribute to the Achievement of Functional Cure in\nChronic Hepatitis B

Peg-IFNα\nis one of the current therapeutic strategies for\nHepatitis B virus (HBV) seroclearance. Nevertheless, the underlying\nmechanisms are not yet adequately understood. The objective of this\nstudy was to explore the potential mechanisms using multiomics approach.\nFor the first time, we revealed the transcriptomic, proteomic, and\nmetabolomic characterizations of Peg-IFNα-induced HBsAg seroclearance.\nWe found that Peg-IFNα caused significant changes during the\ntreatment. Patients who achieved HBsAg seroclearance were characterized\nas having decreased transcriptional activity of genes involved in\nfatty acid metabolism and the glycolysis/gluconeogenesis pathway,\nwith up-regulated expression of fatty acid degradation-related proteins.\nConsistently, mitochondrial TCA cycle metabolites, including citric,\nisocitric, and malic acids, were significantly elevated in patients\nwho achieved HBsAg seroclearance. We also observed up-regulated transcriptional\nactivity of NK cell-mediated cytotoxicity, positive regulation of\nB cell activation, immunoglobulin production, and T cell receptor\ncomplex in functional-cured patients. Conversely, the metabolites\nassociated with unsaturated fatty acid biosynthesis were increased\nin HBsAg persistent patients, and the transcriptional activity of\nimmunoglobulin production and T cell receptor complex was down-regulated\nafter 48 weeks of Peg-IFNα treatment. Our findings provided\nvaluable resources to better understand the process of HBsAg seroclearance\nand shed new light on the pathways to facilitate higher functional\ncure rates for CHB.