Immunometabolic Dysregulation in Preeclampsia: Emerging Roles of Inflammation, Insulin Resistance, Uric Acid, and the Gut Microbiome.

Preeclampsia is a major cause of maternal and perinatal morbidity around the world. It is increasingly recognized as a disorder of systemic immunometabolic dysregulation rather than isolated placental dysfunction. Increasing evidence links chronic inflammation, insulin resistance, and changes in uric acid metabolism to the initiation and progression of preeclampsia. In addition, emerging evidence indicates that maternal gut dysbiosis is an upstream regulator of systemic immune and metabolic dysfunction via the gut-systemic-decidual axis. This review synthesizes current mechanistic, clinical, and translational evidence on the interplay between immune activation, metabolic dysfunction, and uric acid biology in relation to preeclampsia, highlighting emerging biomarkers and therapeutic implications. A narrative review was performed of experimental, epidemiological, and clinical studies found in peer-reviewed journals. The review focused on pathways involving innate and adaptive immune activation, inflammation, insulin signaling abnormalities, endothelial dysfunction, and how uric acid affects placental and vascular biology. Preeclampsia shows increased activation of the innate immune system, a shift toward Th1/Th17 responses, vascular inflammation, and impaired immune tolerance. These immune disturbances combine with pregnancy-associated insulin resistance, exacerbating oxidative stress and endothelial dysfunction, thereby reducing oxygen supply to the placenta. Elevated levels of serum uric acid (SUA), previously regarded as merely a marker of disease severity, are now thought to actively promote inflammasome activation, inhibit nitric oxide (NO), and disrupt trophoblast function. Together, these interconnected pathways form self-reinforcing immunometabolic feedback loops that sustain vascular damage and drive the progression of the disease. Recent studies indicate that changes in the composition of maternal gut microbiota and their metabolites, such as short-chain fatty acids (SCFAs) and endotoxins, can lead to systemic inflammation, endothelial dysfunction, and reduced immune tolerance. Immunometabolic dysregulation provides a comprehensive framework for understanding the pathogenesis of preeclampsia. Integrating inflammatory pathways, insulin resistance, serum uric acid, and alterations in the gut, systemic, and decidual microbiomes may improve risk stratification and facilitate the development of targeted preventive strategies. Nevertheless, well-designed longitudinal and interventional studies are needed to validate these associations, establish causal relationships, and translate emerging evidence into effective prevention and management approaches across diverse populations.