Multiomics Analyses Reveal that Fatty Acid Metabolism and TCA Cycle Contribute to the Achievement of Functional Cure in Chronic Hepatitis B

Abstract

Peg-IFNα is one of the current therapeutic strategies for Hepatitis B virus (HBV) seroclearance. Nevertheless, the underlying mechanisms are not yet adequately understood. The objective of this study was to explore the potential mechanisms using multiomics approach. For the first time, we revealed the transcriptomic, proteomic, and metabolomic characterizations of Peg-IFNα-induced HBsAg seroclearance. We found that Peg-IFNα caused significant changes during the treatment. Patients who achieved HBsAg seroclearance were characterized as having decreased transcriptional activity of genes involved in fatty acid metabolism and the glycolysis/gluconeogenesis pathway, with up-regulated expression of fatty acid degradation-related proteins. Consistently, mitochondrial TCA cycle metabolites, including citric, isocitric, and malic acids, were significantly elevated in patients who achieved HBsAg seroclearance. We also observed up-regulated transcriptional activity of NK cell-mediated cytotoxicity, positive regulation of B cell activation, immunoglobulin production, and T cell receptor complex in functional-cured patients. Conversely, the metabolites associated with unsaturated fatty acid biosynthesis were increased in HBsAg persistent patients, and the transcriptional activity of immunoglobulin production and T cell receptor complex was down-regulated after 48 weeks of Peg-IFNα treatment. Our findings provided valuable resources to better understand the process of HBsAg seroclearance and shed new light on the pathways to facilitate higher functional cure rates for CHB.