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

Kun Lin; Rongxian Qiu; Songhang Wu; Yongbin Zeng; Tianbin Chen; Zhen Xun; Ni Lin; Can Liu; Qishui Ou; Ya Fu

doi:10.1021/acs.jproteome.4c00747

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

J Proteome Res. 2024 Dec 10. doi: 10.1021/acs.jproteome.4c00747. Online ahead of print.

Authors

Kun Lin^{1

2

3}, Rongxian Qiu⁴, Songhang Wu^{1

2}, Yongbin Zeng^{1

2}, Tianbin Chen^{1

2}, Zhen Xun^{1

2}, Ni Lin⁵, Can Liu^{1

2}, Qishui Ou^{1

2}, Ya Fu^{1

2}

Affiliations

¹ Department of Laboratory Medicine, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
² Fujian Key Laboratory of Laboratory Medicine, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
³ Department of Laboratory Medicine, the Affiliated Hospital of Putian University, Putian University, Putian 351100, China.
⁴ Department of Infectious Diseases, the Affiliated Hospital of Putian University, Putian University, Putian 351100, China.
⁵ School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350005, China.

PMID: 39655723
DOI: 10.1021/acs.jproteome.4c00747

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.

Keywords: HBV; HBsAg seroclearance; Peg-IFNα; chronic hepatitis B; citrate cycle (TCA cycle); fatty acid metabolism; functional cure; immunity; multiomics; therapy.