The advent of direct-acting antivirals (DAAs) has transformed chronic hepatitis C (CHC) into a curable disease. However, viral eradication does not eliminate hepatocellular carcinoma (HCC) risk. Residual risk persists, particularly among patients with preexisting fibrosis or metabolic comorbidities. In this issue of Alimentary Pharmacology & Therapeutics, Lin et al. evaluate whether a steatosis-related polygenic risk score (PRS-5) can refine HCC risk stratification after hepatitis C virus (HCV) cure 1. Their findings align with prior evidence implicating hepatic fat–related genetic pathways in postcure oncogenesis. Degasperi et al. demonstrated in DAA-treated cirrhotic HCV patients that a steatosis-related genetic risk score independently predicted de novo HCC (HR ≈2.30), supporting a mechanistic link between lipotoxicity and tumorigenesis even after viral clearance 2. The present study extends this concept beyond strictly cirrhotic populations by evaluating PRS-5 performance in a broader postsustained virologic response (SVR) population, further reinforcing the relevance of steatotic genetic pathways in residual HCC risk. Lin et al. report that PRS-5 is independently associated with incident HCC, even after adjusting for clinical factors such as the Fibrosis-4 (FIB-4) index and body mass index. These findings reinforce the biological plausibility that lipid remodelling genes continue to influence oncogenic pathways despite SVR. Post-SVR molecular persistence, including epigenetic alterations and immune dysregulation, may further amplify this risk 3. Nevertheless, genetic integration into surveillance models requires careful interpretation. Nahon et al. recently showed that adding a 7-SNP genetic risk score to established clinical models in cirrhosis modestly improved discrimination (C-index 0.769 to 0.786) and yielded only fair net benefit on decision-curve analysis 4. This underscores a critical distinction: statistical association does not necessarily equate to meaningful clinical impact. Accordingly, any incorporation of PRS-5 into surveillance algorithms must demonstrate meaningful incremental clinical utility beyond established fibrosis-based markers. The implications extend beyond CHC. As metabolic dysfunction-associated steatotic liver disease (MASLD) emerges as a dominant driver of HCC globally, shared steatosis-related genetic mechanisms may bridge viral and metabolic hepatocarcinogenesis 5, 6. Unlike CHC, MASLD-related HCC frequently arises in non-cirrhotic livers, indicating that existing surveillance strategies may not be sufficient in all risk strata. Integration of genetic susceptibility with metabolic and fibrosis markers may facilitate risk enrichment 7, 8. At present, PRS-5 should be viewed as a complementary tool rather than a replacement for established surveillance frameworks. These results suggest that, once externally validated, PRS-based stratification could support individualised surveillance strategies by identifying higher-risk subgroups. However, prospective validation, calibration across ancestries, and evaluation of decision impact remain essential 9. In the evolving post-SVR and MASLD era, a steatosis-centric genetic approach provides a conceptual framework for precision risk stratification 10. Whether PRS-5 integration will ultimately alter surveillance intensity or modality depends less on hazard ratios alone and more on demonstrable clinical utility. Such implementation requires clearly defined risk thresholds and management pathways. Accordingly, future studies should prioritise prospective validation and rigorous assessment of decision impact. Heechul Nam: writing – original draft. Sung Won Lee: conceptualization, writing – review and editing, project administration. The authors have nothing to report. This article is linked to Lin et al papers. To view these articles, visit https://doi.org/10.1111/apt.70566 and https://doi.org/10.1111/apt.70628. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Nam et al. (Tue,) studied this question.