The cardiovascular risk marker itaconate is sex-dependently associated with legume intake and immune-inflammatory competence in subjects with high BMI

Background Itaconate has received attention as a key immunometabolic mediator produced by activated macrophages, linking cellular metabolism to inflammatory responses. The determinants of circulating itaconate as a cardiovascular risk marker and putative relationships with diet, inflammation, and sex-specific immune responses were assessed given that it remains poorly characterized. Objectives The aim of this investigation was to analyze the determinants of circulating itaconate concentrations involving metabolic associations, with markers of innate immune activation and systemic inflammation, as well as to evaluate the potential modulatory role of dietary patterns—particularly legume consumption—as well as sex-specific differences concerning these relationships in subjects with excessive adiposity. Methods A total of 453 participants were screened in relation to dietary intake, and also anthropometric measurements, biochemical and inflammatory markers. Participants were categorized according to itaconate levels and legume consumption. Multivariable linear regression models were implemented to identify factors associated with circulating itaconate concentrations. Interaction analyses were performed to assess sex-specific associations. Results Circulating itaconate concentrations did not differ across categories of legume intake or adherence to the Mediterranean diet. Baseline characteristics were comparable across groups, with a borderline inverse association with IL-6 levels (p = 0.053). Higher legume consumption was associated with a healthier lifestyle profile and lower adiposity, but not with circulating itaconate. In multivariable analyses, monocyte counts were independently associated with circulating itaconate, while IL-6 showed an independent inverse association. No associations were observed for age, sex, adiposity, dietary variables, or other inflammatory markers. A significant interaction between itaconate and sex was identified for monocyte counts (p = 0.025), with an inverse association observed in men but not in women. Conclusions Circulating itaconate appears to reflect innate immune activation rather than dietary exposure per se . Association with monocyte-related phenotypes and systemic inflammation, together with marked sex-specific differences, supports a dependent role of itaconate within immunometabolic interactions. The findings highlight notable sex-specific immune responses, underscoring the importance of considering biological sex in understanding variations in immune function in the context of precision medicine.