CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND AND OBJECTIVE: Despite direct-acting antiviral (DAA) therapies achieving sustained virologic response (SVR) rates exceeding 95%, hepatocellular carcinoma (HCC) risk persists in cured hepatitis C virus (HCV) patients, particularly those with advanced fibrosis or concurrent metabolic dysfunction-associated steatotic liver disease (MASLD). This clinical paradox implies that HCV induces durable oncogenic molecular alterations independent of active viral replication, fundamentally challenging the notion that virologic cure equates to biological liver cure. This review aims to delineate the molecular mechanisms underlying this residual risk and to identify rational targets for chemoprevention in the post-SVR era. METHODS: A narrative literature search was conducted across PubMed/MEDLINE, Scopus, and Web of Science for articles published between January 2015 and December 2025. The search strategy utilized a combination of keywords encompassing the pathogen (hepatitis C virus, HCV), clinical endpoints (sustained virologic response, SVR, hepatocellular carcinoma, HCC), and specific oncogenic mechanisms of interest, including epigenetic alterations, metabolic reprogramming, immune exhaustion, fibrosis, and lysyl oxidase-like 2 (LOXL2). Studies providing original mechanistic data in human post-SVR tissue, prospective or retrospective clinical cohort outcomes, validated animal models, or relevant meta-analyses in adult populations were included. Case reports, editorials, and non-peer-reviewed sources were excluded. KEY CONTENT AND FINDINGS: Four interconnected post-SVR oncogenic mechanisms are examined: (I) epigenetic scarring via persistent H3K27 acetylation at the SPHK1 locus sustaining oncogene expression; (II) metabolic reprogramming through the SPHK1/S1P/SREBP1c axis, driving constitutive de novo lipogenesis (DNL), reductive stress, and oxidative DNA damage; (III) immunological dysfunction characterized by TOX-driven CD8+ T-cell exhaustion and lipid-mediated natural killer (NK) cell paralysis, collectively abrogating tumor surveillance; and (IV) stromal remodeling via LOXL2-mediated collagen cross-linking perpetuating YAP/TAZ mechanotransduction. MASLD comorbidity synergistically amplifies all four mechanisms, effectively doubling HCC incidence. CONCLUSIONS: SVR represents a critical milestone, not a biological cure. These molecular scars synergize with MASLD to sustain a permissive oncogenic microenvironment long after viral eradication. Achieving true "molecular remission" will require longitudinal biorepositories for causal validation, clinically deployable multi-omics biomarker panels, and rigorously designed chemoprevention trials targeting residual epigenetic, metabolic, immune, and stromal sequelae of HCV infection.