An Investigative Study of LGALSL and HLA‐DRB1 as Prognostic Biomarkers and Therapeutic Targets in Chronic Hepatitis B Patients With Persistent HBV DNA Viremia Under Entecavir Treatment

Despite significant advances in chronic hepatitis B (CHB) treatment, some patients receiving entecavir (ETV) still experience poor clinical outcomes. Identifying host factors contributing to ETV anti-HBV failure in CHB patients with persistent HBV DNA positivity is crucial for developing targeted therapies. We conducted a comprehensive study using univariate and reverse Mendelian randomization (MR), incorporating sequencing data and publicly available genetic data, followed by gene set variation analysis (GSVA), gene set enrichment analysis (GSEA) and immune cell infiltration analysis to systematically explore causal associations between host factors and CHB. Univariate MR analyses revealed a significant inverse association between increased HLA-DRB1 levels and CHB risk (odds ratio [OR] 0.607, 95% confidence interval [CI] 0.478-0.771, p = 0.00004), while increased LGALSL levels were significantly associated with a heightened risk of poor CHB prognosis (OR 1.110, 95% CI: 1.017-1.212, p = 0.01885), as estimated using the inverse variance weighting (IVW) method. Analysis of immune cell infiltration showed significantly higher HLA and mast cell levels in the poor prognosis group. HLA-DRB1 showed a significant positive correlation with HLA, whereas LGALSL showed a significant negative correlation. Compared to patients with favorable prognoses, those with poor prognoses exhibited significantly higher serum LGALSL levels (ELISA), lower HLA-DRB1 expression in peripheral blood mononuclear cells (PBMCs) (qPCR), and significantly increased LGALSL expression in liver tissue (IHC). Therefore, LGALSL and HLA-DRB1 may serve as potential prognostic biomarkers for CHB patients receiving ETV, providing novel avenues for diagnosis and treatment.