MBOAT7 rs641738 TT genotype is associated with poorer survival in MASLD-related hepatocellular carcinoma

Introduction: Genetic variants involved in lipid and glucose metabolism have been implicated in liver disease progression and hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, their prognostic role in patients with established HCC remains unclear. We aimed to investigate the association between MASLD-related genetic variants and overall survival (OS) in patients with MASLD-related HCC. Methods: We retrospectively evaluated 258 patients with MASLD-related HCC (median age: 73, 49-79 years; male sex: 86.8%); most patients had a diagnosis of early tumor (BCLC 0/A: n = 162; 62.8%). PNPLA3 rs738409, TM6SF2 rs58542926, MBOAT7 rs641738, GCKR rs780094, and HSD17B13 rs72613567 variants were genotyped. An independent cohort of viral-related HCC (n = 384) was analysed for exploratory comparison. Overall survival (OS) was evaluated using Kaplan-Meier analysis and multivariable Cox regression. Results: Among the investigated gene variants, only the MBOAT7 rs641738 TT genotype was associated with reduced OS in patients with MASLD-related HCC compared to CC/CT carriers (19.8 vs. 32.2 months; p = 0.006). At multivariable analysis, MBOAT7 rs641738 TT genotype retained a nominal association with poorer OS after adjustment for age, sex, tumor burden, and metabolic cofactors (aHR = 1.61, 95% CI 1.05-2.46; p = 0.028). Conversely, OS did not differ according to MBOAT7 rs641738 genotype in the exploratory viral-related HCC comparison cohort (p = 0.449). Conclusions: MBOAT7 rs641738 genotype was associated with poorer OS in patients with MASLD-related HCC. This finding was not observed in an exploratory viral-related HCC comparison cohort, but between-cohort differences limit etiological interpretation. These results should be considered hypothesis-generating and require external validation.