Sex-divergent metabolic pathways in the association between vitamin D status and metabolic-associated fatty liver disease

Vitamin D insufficiency has been linked to metabolic-associated fatty liver disease (MAFLD), but whether biological sex shapes this relationship remains poorly characterized. Building on a primary report that established this association in the pooled cohort, we tested whether the association and its candidate metabolic pathways differ by sex and, using age as a proxy for estrogen exposure, whether the association in women varies across the adult life course to clarify pathophysiological differences and therapeutic implications between men and women. In this cross-sectional secondary analysis, we analyzed 22,476 Korean adults with metabolic dysfunction (16,320 men and 6156 women). Sex-stratified multivariable logistic regression estimated the association between vitamin D insufficiency (<20 ng/mL) and MAFLD, and mediation analyses explored the contribution of individual metabolic pathways in each sex. Age was used as a proxy for estrogen status to test effect modification of the association in women. Vitamin D insufficiency was associated with higher MAFLD risk in both sexes, with a stronger association in women (odds ratio [OR]: 1.53, 95% confidence interval [CI]: 1.18-1.98, P = .001) than in men (OR: 1.32, 95% CI: 1.22-1.43, P < .001). Insulin resistance was the predominant statistical mediator in both sexes but contributed more in women (58.6% vs 42.3% in men), whereas systemic inflammation was a significant mediator only in women (19.3%), and lipid metabolism and adiposity were more prominent in men. When age was used as an estrogen proxy, the association in women was numerically strongest in the youngest reproductive-age stratum and attenuated at older ages, although the vitamin D-by-age interaction was not statistically significant. Among women with high-risk alcohol consumption, the point estimate was higher (OR: 4.37, 95% CI: 1.79-10.67, P = .001), although this stratum was small (n = 308) and the estimate imprecise. Vitamin D insufficiency is associated with MAFLD in both sexes, but more strongly in women, and the candidate metabolic pathways differ between the sexes. These observations suggest that sex-specific strategies - targeting insulin sensitivity and inflammation in women and lipid metabolism and weight in men - may merit evaluation for MAFLD prevention and management. Because the design is cross-sectional, these associations are hypothesis-generating and require longitudinal confirmation.