The role and underlying mechanism of FABP4 dysregulation mediated by m6A modification in unexplained recurrent spontaneous abortion

Unexplained recurrent spontaneous abortion (URSA) poses a significant clinical challenge with an elusive pathogenesis. FABP4 is crucial for lipid homeostasis and placental development, but its specific role and regulatory mechanism in URSA remain unclear.

FABP4 expression was analyzed in human placental tissues from URSA patients and control groups. The functional role of FABP4 was investigated using Fabp4-knockout mouse models and trophoblast cell lines. Mechanistic studies employed Seahorse metabolic analysis, Raman spectroscopy, methylated RNA immunoprecipitation qPCR (MeRIP-qPCR), and single-cell RNA sequencing to assess mitochondrial function and lipid metabolism.

FABP4 was significantly down-regulated in placental tissues from URSA patients. In vivo and in vitro models confirmed that FABP4 deficiency leads to trophoblast dysfunction. Mechanistically, FABP4 expression was regulated by m6A methylation modifications. Downregulation of the m6A demethylase FTO increased m6A levels on FABP4 mRNA, inhibiting its expression. Concurrently, downregulation of the m6A reader IGF2BP3 reduced FABP4 mRNA stability. This dysregulation of FABP4 disrupted intracellular lipid homeostasis in trophoblast cells, leading to suppressed mitochondrial oxidative phosphorylation, activated oxidative stress, and inhibited SOD2 expression, ultimately contributing to the pathogenesis of URSA.

This study identifies FABP4 deficiency as a critical event in URSA pathogenesis, driven by an m6A-mediated epigenetic mechanism involving FTO and IGF2BP3. FABP4 downregulation disrupts trophoblast lipid metabolism and mitochondrial function. These findings offer novel insights into URSA and suggest FABP4 as a potential therapeutic target for clinical intervention.