Evolutionary and functional landscape of HBx mutations in genotype D1 HBV: comparative insights from acute infection, chronic hepatitis, and HCC

HBV infection remains a major global health burden and a leading cause of hepatocellular carcinoma (HCC), with viral genetic variability contributing to the heterogeneity of clinical outcomes. Among HBV proteins, HBx functions as a multifunctional regulatory protein involved in viral replication, host transcriptional regulation, apoptosis, immune signaling, and oncogenic pathways. Although HBx biology has been extensively investigated, most mechanistic insights are derived from genotype B and C infections, while genotype D—particularly subgenotype D1—remains comparatively underrepresented. This narrative review provides an integrative synthesis of reported HBx mutational patterns across distinct clinical contexts of HBV infection, including acute infection, chronic hepatitis B, and HBV-related HCC, with particular emphasis on genotype D1–dominant populations from the Middle East. The review incorporates findings from previously published phase-specific studies together with relevant external literature to explore how HBx variability may relate to functional domains and disease-associated molecular patterns. Mutations are discussed in the context of major HBx functional regions, including the N-terminal regulatory region, the transactivation domain, the H-box/DDB1-binding motif, and the BH3-like region. Structural modeling, protein–protein interaction network analysis, and phylogenetic contextualization are used as conceptual and illustrative frameworks to interpret reported variants without inferring direct causality. Reported HBx variability appears to preferentially involve structurally flexible and interaction-rich regions. Recurrent substitutions, particularly involving glycine residues, are more frequently reported in acute and chronic infection settings, whereas HCC-associated variants more commonly involve C-terminal alterations and truncation events. Collectively, these observations support a hypothesis-generating framework in which HBx functional plasticity may reflect adaptive virus–host interactions under selective pressures rather than a linear oncogenic mechanism driven by individual mutations alone. Importantly, no new experimental or clinical data are presented, and all interpretations are derived from previously published studies and in silico analyses. By emphasizing genotype D1–specific evolutionary characteristics and addressing a geographical gap in HBV research, this review may provide a useful conceptual basis for future functional investigations, genotype-stratified analyses, and translational studies in HBV-associated liver disease.