The HCV-Melanoma Paradox: First Multi-Cohort and Molecular Net-Work Analysis Reveals Lower Incidence but Worse Outcomes—Integrating Clinical, Real-World, and In Silico Data

<i>Background and Objectives</i>: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. <i>Materials and Methods</i>: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. <i>Results</i>: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, <i>p</i> = 0.014), recurrence (65.5% vs. 39.8%, <i>p</i> = 0.020), and mortality (65.5% vs. 23.0%, <i>p</i> < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, <i>p</i> < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, <i>p</i> < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. <i>Conclusions</i>: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions.