FABP4 as an immunometabolic hub in preeclampsia: from maternal-fetal interface to systemic inflammation.

Preeclampsia (PE) is a multisystem vascular disease that occurs specifically during pregnancy, and the understanding of its pathogenesis is gradually shifting from the traditional "placental ischemia-endothelial injury" model to immunometabolic disorders. In this article, we propose a conceptual framework positioning fatty acid binding protein 4 (FABP4) as an immunometabolic hub in the pathogenesis of PE. Clinical studies suggest that FABP4 is significantly elevated in preeclamptic placentas and maternal circulation; epigenetic derepression via miR-148a/152-mediated DNMT1 downregulation contributes to this placental upregulation. Leveraging its primary identity as an intracellular lipid chaperone, we hypothesized a spatiotemporal cascade linking local immune imbalance to systemic vascular injury. Intracellularly, drawing upon highly conserved lipotoxic pathways established in non-pregnancy models, we extrapolate that FABP4 participates in the regulation of the immune microenvironment at the maternal-fetal interface by modulating macrophage polarization toward the M1-type and activating the NLRP3 inflammasome axis; a recent study in an EVT-derived cell line (HTR-8/SVneo) demonstrated that pharmacological inhibition or siRNA knockdown of FABP4 impairs mitochondrial membrane potential, reduces ATP synthesis, and increases oxidative stress, resulting in proliferative arrest. These findings position FABP4 as a viability factor for trophoblast-like cells under metabolic stress, though direct validation in primary EVTs is still required. Extracellularly, upon entering maternal circulation, FABP4 may trigger systemic inflammatory cascade responses and induce endothelial dysfunction. While single-cell transcriptomic studies have revealed significant reprogramming of lipid metabolism-related gene expression in PE placental immune cells, direct single-cell quantification of FABP4 across specific placental subpopulations remains to be performed. Consequently, by integrating macroscopic clinical data with these microscopic intercellular networks, we frame the FABP4-driven axis as a plausible mechanistic convergence, highlighting its promise as a critical translational target for immunometabolic intervention.