FABP4 is highly expressed in preeclamptic placentas and regulates trophoblast lipid metabolism, mitochondrial function, and oxidative stress in vitro.

OBJECTIVE: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by abnormal placental development and systemic endothelial dysfunction. Previous studies have suggested that fatty acid binding protein 4 (FABP4) is involved in lipid metabolism and oxidative stress regulation in various metabolic and cardiovascular diseases. However, its specific role and underlying mechanisms in PE, particularly in trophoblast function and mitochondrial homeostasis, remain unclear. This study aims to investigate the role of FABP4 in the pathogenesis of PE by exploring its effects on trophoblast cell function and mitochondrial oxidative stress through regulating lipid metabolism. METHODS: Placental tissues were collected from 25 PE patients and 21 healthy pregnant women to detect FABP4 expression using qRT-PCR. In vitro experiments were conducted on HTR-8/SVneo trophoblast cells. FABP4 was silenced by siRNA (si267) or inhibited by BMS309403. Cell proliferation was assessed via CCK-8 and EdU assays. RNA sequencing was performed to analyze related pathways. Free fatty acid (FFA) levels, reactive oxygen species (ROS) production, mitochondrial membrane potential, and ATP content were measured to evaluate lipid metabolism, oxidative stress, and mitochondrial function. Statistical analyses were done using t-test and one-way ANOVA. RESULTS: FABP4 expression was significantly higher in placental tissues of PE patients compared to controls. Both FABP4 inhibitor and siRNA knockdown suppressed HTR-8/SVneo cell proliferation. Transcriptomic analysis identified that FABP4 was enriched in pathways related to lipid metabolism (e.g., Lipid and atherosclerosis) and mitochondrial function, with key genes (e.g., PPARγ) showing differential expression. FABP4 inhibition or silencing reduced intracellular cytosolic FFA levels, increased ROS production, decreased mitochondrial membrane potential, and lowered ATP content. CONCLUSION: FABP4 mRNA expression is elevated in placentas from preeclamptic patients. In vitro, reduction of FABP4 impairs trophoblast proliferation, which is associated with disrupted cytosolic FFA metabolism, subsequent mitochondrial dysfunction (decreased membrane potential, reduced ATP), and increased oxidative stress (elevated ROS). These findings suggest FABP4-related pathways may be involved in placental lipid handling and mitochondrial homeostasis; however, since this study only detected FABP4 mRNA (not protein) and used in vitro models, additional protein-level validation and in vivo studies (e.g., PE animal models) are required to establish causality and evaluate therapeutic potential.