Beyond silencing: integrative multi-omics and spatial profiling unravel the systems-level role of piRNAs in HBV-driven Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) driven by chronic hepatitis B virus (HBV) infection remains a global health challenge, with late diagnosis and limited therapeutic options underscoring the need for novel biomarkers and mechanistic insights. Once considered guardians of the germline, PIWI-interacting RNAs (piRNAs) are now emerging as key somatic regulators of chromatin, transcription, and signaling in cancer. This review considers HBV a plausible perturbant of the hepatic piRNA ecosystem, through viral integration, epigenetic remodeling, and altered intercellular communication. Unlike prior reviews that mainly catalog PIWI/piRNA findings in HCC or summarize broader liver-cancer multi-omics, this article advances a testable HBV-piRNAome disruptor model with three falsifiable predictions: HBV integration and 3D genome rewiring alter piRNA-cluster output, HBx/HBsAg-driven chromatin remodeling shifts PIWI/piRNA stoichiometry, and spatially restricted tumor, stromal, and immune niches generate distinct piRNA signatures that can be mapped in matched tissue and plasma. This framework is intended to help move from association to testable mechanism and, where supported, to clinically anchored validation. This is a conceptual narrative review rather than a systematic review or meta-analysis; therefore, no PRISMA flow diagram is provided, and the cited literature was selected for conceptual and mechanistic relevance. We argue that decoding HBV-driven hepatocarcinogenesis requires linking piRNA dysregulation to the biological consequences of HBV integration, HBx-driven epigenetic remodeling, and niche-specific fibrogenic and immune reprogramming; spatial multi-omics should be used to localize these mechanisms to the relevant cell types and tissue compartments. Such systems-level profiling can help nominate candidate biomarkers and therapeutic vulnerabilities for future validation, but clinical translation will still require prospective cohorts, standardized EV/small-RNA workflows, rigorous functional confirmation, and formal safety/regulatory review before use in patients.