Curcumin Attenuates Decidual Stromal Cell Ferroptosis and Restores Impaired Decidualization in Recurrent Spontaneous Abortion by Targeting BRD4

ABSTRACT

Recurrent spontaneous abortion (RSA) is a major reproductive health challenge with limited clinical options. Curcumin, a natural polyphenol widely consumed as a dietary supplement, has shown promise in improving pregnancy outcomes; however, its specific molecular targets remain obscure due to its broad bioactivity. This study aimed to define curcumin's impact on RSA and identify its direct molecular target to provide a mechanistic basis for its nutritional application. We employed an integrated approach combining phenotypic analysis in the RSA mouse model and target discovery in human endometrial stromal cells. Target identification was performed using unbiased Limited Proteolysis‐Mass Spectrometry (LiP‐MS). The interaction between curcumin and the identified target, BRD4, was confirmed through molecular docking, dynamics simulations, functional genetics, and chromatin immunoprecipitation (ChIP‐qPCR). Functional outcomes were assessed by measuring key ferroptosis markers and mitochondrial morphology using transmission electron microscopy. Decidualization was analyzed in both mouse tissues and cells subjected to a decidualization and ferroptosis induction protocol. Curcumin significantly reduced embryo resorption and restored decidual morphology and marker expression (PRL and IGFBP1) in RSA mice. LiP‐MS analysis in human decidual stromal cells identified ferroptosis as the primary pathway targeted by curcumin. Both in vivo and in vitro validation showed that curcumin inhibits ferroptosis, decreasing lipid peroxidation, restoring glutathione balance, and preserving mitochondrial integrity, which in turn rescued decidual marker expression. Proteomic integration with ferroptosis databases identified BRD4 as a central hub. Mechanistically, curcumin binds BRD4, thereby suppressing BRD4‐driven expression of TFRC and ACSL4, which blocks ferroptosis and rescues decidual markers. This research uncovers a BRD4‐driven ferroptosis pathway as a key pathogenic mechanism in RSA. Our results demonstrate that curcumin acts as an epigenetic modulator by directly targeting BRD4, thereby suppressing this pro‐ferroptotic transcriptional program. These findings provide critical mechanistic evidence supporting curcumin as an evidence‐based nutritional intervention for RSA.