(1) Background: Chronic hepatitis B (CHB) is a widely prevalent chronic liver disease, with a particularly high incidence in China. Recent studies indicate that external influences like a high-fat, high-sugar diet and high temperature and humidity may alter the hepatic immune microenvironment in CHB and hasten liver injury progression in patients. Nonetheless, the cumulative effect of these combined factors on liver damage and the immune remodeling process, along with its regulatory mechanisms, remains uncertain. (2) Objective: This research seeks to clarify the impact of simultaneous exposure to a high-fat, high-sugar diet and a high-temperature, high-humidity environment on CHB liver injury and its primary immunometabolic pathways. (3) Methods: This research employed recombinant adenovirus AdrcccDNA to establish a CHB mouse model (M group), and subsequently developed a combined exposure model through intervention with a high-fat, high-sugar diet and a high-temperature, high-humidity environment (NWS group). Subsequently, multi-omics analysis, WGCNA, immune infiltration analysis, and in vivo and in vitro experiments were employed to evaluate the effects of a high-fat and high-sugar diet combined with high-temperature and high-humidity exposure on the progression of CHB. (4) Results: HE staining, virology, and other results showed that combined exposure worsened liver injury and increased viral replication in CHB mice. WGCNA and immune infiltration analysis revealed CD4⁺ T cells as the key differential immune cells and identified 36 associated core mRNAs. Combined analysis revealed that miR-340-5p was significantly negatively correlated with Psat1 expression and highly associated with the proliferation and function of memory CD4⁺ T cells. In vivo validation indicated that in the NWS group, Psat1 levels were reduced, miR-340-5p levels were elevated, and the percentage of memory CD4⁺ T cells was diminished. After in vitro transfection with miR-340-5p mimics, Psat1 levels were downregulated in AML12 and primary CD4⁺ T cells, indicating that miR-340-5p negatively influences Psat1. (5) Conclusions: This study demonstrates that combined exposure to a high-fat, high-sugar diet and a high-temperature, high-humidity environment may worsen CHB liver injury through miR-340-5p/Psat1-mediated immunometabolic regulation.

(1) Background: After HBV infection, viral transcripts and host RNA form a multi-layered interwoven regulatory network. However, a comprehensive map encompassing mRNA, miRNA, lncRNA, and circRNA is still lacking. This absence complicates the systematic explanation of the molecular mechanisms driving immune escape and metabolic reprogramming during the persistent infection stage. (2) Methods: In this study, we established a mouse model of chronic HBV infection and analyzed the differential expression of mRNA, miRNA, lncRNA, and circRNA through whole transcriptome sequencing (WTS). We constructed a competing endogenous RNA (ceRNA) network to systematically evaluate the overall impact of HBV on the host’s immune-metabolic pathways. (3) Results: RNA sequencing results indicated that HBV infection significantly up-regulated 194 mRNAs, 18 miRNAs, 184 lncRNAs, and 28 circRNAs, while down-regulating 42, 16, 122, and 31 corresponding transcripts, respectively. The differentially expressed genes were primarily enriched in pathways related to metabolism, immunity/inflammation, and signal transduction-ligand receptor interactions. Furthermore, the competitive endogenous RNA networks of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA constructed on this basis further identified miR-185-3p as a key core node. (4) Conclusions: In this study, based on whole transcriptome data, the gene expression profiles of rcccDNA/Ad-infected Alb-Cre transgenic mice (chronic HBV infection model) and normal Alb-Cre mice were systematically compared, and the core regulatory factor miR-185-3p of key differentially expressed genes was screened. The microRNA is expected to provide a new target for the precise treatment of chronic hepatitis B by targeted intervention of viral replication and high liver inflammation.