Landscape and biogenesis of piRNAs in HBV-associated hepatocarcinogenesis: from repetitive elements to oncogenic...

Hepatitis B virus (HBV) is a leading cause of hepatocellular carcinoma (HCC), driving oncogenesis through genomic integration, chronic inflammation, and epigenetic dysregulation. While DNA methylation and histone modifications have been studied extensively, the role of PIWI-interacting RNAs (piRNAs), small non-coding RNAs traditionally linked to germline transposon silencing, remains underexplored in HBV-associated HCC. This review synthesizes emerging evidence that HBV infection remodels the hepatic piRNA landscape through viral integration, hepatitis B virus X protein (HBx)-mediated protein interactions, and inflammation-induced transcriptional rewiring. Reported piRNA changes suggest roles in transposable element derepression, epigenetic silencing of tumor suppressors, post-transcriptional targeting of oncogenic mRNAs, and intercellular communication via exosomes; however, most studies remain correlative and lack direct PIWI-binding validation or mechanistic loss-of-function experiments. We further discuss the translational potential of piRNAs as non-invasive biomarkers for early detection and prognosis, and as therapeutic targets through PIWI inhibition, epigenetic editing, or antisense oligonucleotides. By bridging molecular mechanisms with clinical implications, this review proposes a hypothesis-generating framework in which HBV reshapes the hepatic piRNA landscape through viral integration, HBx-mediated protein interactions, and inflammation-associated epigenetic regulation, thereby providing a strategic foundation for future mechanistic studies, diagnostic development, and therapeutic exploration in HBV-driven hepatocarcinogenesis.