Translational Hepatology From Bedside to Global Policy: How Robust Clinical and Translational Research Reshapes Global Practice Guidelines and Patient Outcomes

ABSTRACT Over four decades, translational hepatology has evolved from empirical observations into an evidence‐driven discipline. This review synthesizes key bedside discoveries, mechanistic studies, prospective cohorts, cross‐regional health‐economic evaluations, and landmark randomized controlled trials (RCTs) by our team that have helped to reshape regulatory drug approvals, Boxed Warnings, and international practice guidelines across APASL, AASLD, and EASL. First, clinical trials established the biphasic model and risk predictors of immunosuppression‐induced hepatitis B virus (HBV) reactivation, proving that pre‐emptive nucleos(t)ide analogue (NUC) prophylaxis prevents liver failure and antineoplastic disruptions. Second, multinational Phase III registration trials of finite 48‐week pegylated interferon alfa‐2a (Peg‐IFN α‐2a) in chronic hepatitis B (CHB)—combined with intrahepatic cccDNA kinetics, adoptive immunity transfer, and 30‐year Asia‐Pacific Markov health‐economic modeling—established response‐guided rules and validated finite Peg‐IFN switch/add‐on strategies as clinically dominant and cost‐effective. Third, prospective cohorts uncovered direct‐acting antiviral (DAA)–induced HBV reactivation during HCV clearance, establishing mandatory regulatory Boxed Warnings and pre‐DAA screening. Fourth, the Phase III HIMALAYA study and pooled Greater China (Mainland China, Hong Kong, Taiwan) cohorts validated the STRIDE regimen (single‐dose tremelimumab plus regular durvalumab) as frontline dual immunotherapy for unresectable hepatocellular carcinoma (uHCC), establishing marked survival benefit in HBV‐predominant populations (median OS 25.26 vs. 14.09 months) alongside a vascular endothelial growth factor (VEGF)–free standard for cirrhotic portal hypertension within APASL guidelines. Finally, translational insights across metabolic dysfunction, COVID‐19, ACLF, artificial intelligence (AI), and functional cure frameworks inform the APASL 2026 “treat‐all” CHB paradigm.