Hepatitis B virus (HBV) infection remains a major global health burden, affecting over 296 million people worldwide and causing approximately 820,000 deaths annually due to complications such as cirrhosis and hepatocellular carcinoma [1,2]. Chronic HBV infection is characterized by persistent viral replication, dysregulated immunity, and sustained hepatic inflammation, which collectively drive disease progression [3,4]. Macrophages are key regulators of immune balance and tissue homeostasis within the hepatic microenvironment [5,6]. They exhibit high phenotypic plasticity, with HBV infection associated with a shift toward M2 polarization, characterized by increased surface marker expression and enhanced anti-inflammatory cytokine production in both human and mouse models [7]. This M2-like polarization has been linked to immune evasion and viral persistence, potentially through processes such as fibrosis promotion and alterations of the tissue microenvironment [8]. However, the molecular mechanisms underlying HBV-associated M2 polarization—particularly the roles of post-translational modifications (PTMs) and metabolic rewiring—remain poorly understood.

Protein lysine acetylation is a key post-translational modification (PTM) regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). It influences macrophage function by modulating protein structure and activity, thereby affecting transcriptional regulation, signaling pathways, and cellular metabolism [9]. As a widespread regulator of protein function, lysine acetylation participates in diverse biological processes, including metabolic control, gene expression, and cell fate determination [10]. For example, acetylation can modulate metabolic enzymes in plants independently of transcript or protein abundance [11], and contributes to site-specific histone modification dynamics during the eukaryotic cell cycle [12]. M2 macrophage polarization is frequently accompanied by alterations in acetylation status; however, the acetylation landscape associated with HBV-induced macrophage polarization toward an M2 phenotype remains largely uncharacterized. Metabolic reprogramming is closely linked to macrophage polarization, with M1 macrophages preferentially relying on glycolysis, whereas M2 macrophages depend more on oxidative phosphorylation and lipid metabolism [7,13,14]. Although HBV has been reported to influence glycolytic pathways in M2 macrophages, whether lipid metabolism is similarly affected remains unclear, despite its critical roles in membrane biosynthesis, signaling, and energy storage. The potential interplay between acetylation and lipid metabolism may contribute to M2 polarization, but this possibility has not yet been experimentally validated.

Current understanding of HBV-induced M2 macrophages remains limited by insufficient acetylome data, incomplete knowledge of the potential links between acetylation and lipid metabolic reprogramming, and unclear pathological roles in HBV-related liver disease. Characterizing their acetylation profiles and metabolic features may help address these gaps. Here, we employed integrated multi-omics approaches and functional assays to systematically profile acetylation-associated metabolic changes in these macrophages, aiming to provide insights into HBV pathogenesis and potential therapeutic targets. The workflow of this study is illustrated in the graphical abstract.