Proteomic Signatures of Hepatitis B Virus Mutations Reveal Genotype-Specific Host Responses and Biomarker Candidates

Hepatitis B virus (HBV) remains a global health challenge, with viral genetic heterogeneity and mutation-driven resistance complicating treatment outcomes. While previous genomic and transcriptomic studies have characterized HBV mutations, the proteomic consequences of these variants remain underexplored. In this study, we applied liquid chromatography- mass spectrometry (LC-MS)-based proteomics and systems biology approaches to serum samples from 60 HBV-infected patients, stratified by mutation-defined genotype signatures. Four genotype groups were generated, including those harboring mutation related to liver disease progression (rt269/s184) and basal core promoter/precore mutations (A1762T/G1896A). Comparative analyses of 406 high-abundance plasma proteins revealed distinct proteomic signatures, particularly in the ##AG group lacking mutation related to liver disease progression motifs. This group exhibited elevated CRISPLD2 and HSPD1 expression, implicating a dual axis of anti-inflammatory buffering and chaperone-mediated viral processes. Network and co-expression analyses identified modules enriched in focal adhesion, extracellular matrix remodeling, angiogenesis, and PI3K/Akt signaling--pathways tightly linked to hepatocarcinogenesis. Protein-protein interaction enrichment further highlighted disruption of chaperone networks, cytoskeletal regulation, and unfolded protein response. These findings provide molecular evidence for genotype-specific host-virus interactions, nominate CRISPLD2 and HSPD1 as biomarker candidates, and suggest therapeutic strategies targeting PI3K/Akt and microenvironmental pathways. Our results underscore the value of proteomics in refining genotype-informed risk stratification and personalized management in chronic HBV.