Background/Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a multifactorial origin involving genetic, epigenetic, and environmental determinants as well as some risk factors. Genetic predisposition has been quantified through polygenic risk scores (PRS), which integrate the cumulative effect of multiple single nucleotide variants (SNVs) associated with disease risk. Despite extensive research on immune and inflammatory pathways in SLE, the interplay between genetic susceptibility and metabolic dysfunction remains poorly understood. This study aimed to explore associations between SLE-related PRS and metabolic, inflammatory, and clinical parameters in adults participating in the METAINFLAMACIÓN-CM project (Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain). Methods: Ninety-three participants were included: 56 SLE patients and 37 individuals with metabolic syndrome (MetS) as a reference group. PRS were computed based on validated lupus-associated SNVs. Results: SLE patients showed a distinct metabolic profile compared with the MetS group, characterized by lower BMI, visceral fat, blood pressure, glucose, and liver enzyme levels. Within the SLE cohort, PRS values varied markedly and correlated with specific clinical and biochemical features. Linear regression models revealed a significant inverse association between PRS in SLE and ferritin levels, whereas other metabolic and inflammatory markers (glucose, IL-6, LDL, CRP, neutrophils) were directly influenced by clinical factors. Conclusions: Polygenic predisposition contributes to variability in SLE metabolic phenotype but does not independently drive most inflammatory parameters. SLE patients displayed metabolic and inflammatory alterations relevant to cardiovascular risk, highlighting the importance of comprehensive cardiometabolic assessment. Integrating PRS with metabolic profiling may support precision personalized management and improve cardiovascular risk evaluation in SLE.

Background/Objectives: Chronic inflammation accompanies obesity, but correlations of longitudinal changes during dietary follow-up remain unclear. We described inflammatory profiles and examined associations of baseline ferritin and body composition with changes during a 32-week energy-restricted Mediterranean-style intervention. Methods: This prospective cohort included 190 adults classified as healthy overweight (n = 49), long COVID with overweight (n = 108), or metabolic syndrome (MS) with overweight (n = 33); 61 healthy normal-weight participants without long COVID or metabolic syndrome contributed to baseline comparisons only. The program prescribed a 30% energy deficit using a Mediterranean-style food-exchange system. Anthropometric, biochemical, inflammatory, lifestyle, and hepatic markers were assessed. MANOVA and multivariable regression examined inflammatory profiles and ferritin-change correlates. Results: Participants with overweight/obesity had a less favorable metabolic and inflammatory profile than normal-weight participants. Baseline ferritin was 100.5 (53.5–178.5), 76.0 (34.0–137.0), and 149.5 (102.0–245.0) ng/mL in the healthy overweight, long-COVID, and MS groups, respectively (omnibus p < 0.001). Mean changes were 8.0 ± 36.4, 3.3 ± 32.6, and −22.0 ± 58.8 ng/mL, respectively (omnibus p = 0.039), with the MS group showing greater decreases. Sex and muscle mass were associated with the multivariate inflammatory profile (both p < 0.001). Clinical group, baseline ferritin, muscle-mass change, MEDAS change, and Fatty Liver Index change were associated with ferritin change, although explanatory performance was limited (adjusted R² = 0.16). Conclusions: Baseline ferritin and body composition were correlates of heterogeneous inflammatory-metabolic profiles and ferritin changes. These hypothesis-generating associations do not establish causal or mechanistic effects and require controlled confirmation with comprehensive iron-status assessment.

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.