CircCOL3A1 Drives Trophoblast Ferroptosis Through TIAL1-p53 Axis to Promote Preeclampsia Progression.

Preeclampsia (PE) is a major pregnancy-specific disorder driven by impaired trophoblast function, placental hypoxia, and excessive oxidative stress. Ferroptosis has recently emerged as a key contributor to placental pathology; however, the upstream regulatory mechanisms that activate ferroptosis in trophoblasts remain incompletely defined. Circular RNAs (circRNAs) have been implicated in trophoblast dysfunction, yet the ferroptosis-related circRNA network in PE is largely unexplored. This study investigated whether circCOL3A1 regulates p53-mediated ferroptosis in trophoblasts and contributes to PE pathogenesis. CircCOL3A1 expression was examined in placental tissues and HTR-8/SVneo cells. Hypoxia and hypoxia/reoxygenation models were used to mimic PE-associated stress in vitro. Loss- and gain-of-function assays, ferroptosis measurements, RNA pull-down, RIP, FISH, and Actinomycin-D stability analyses were performed to elucidate the circCOL3A1/TIAL1/p53 axis. A reduced uterine perfusion pressure (RUPP) rat model was used to evaluate the in vivo effects of circCOL3A1 knockdown. CircCOL3A1 was significantly elevated in PE placentas and hypoxia-treated trophoblasts, exhibiting cytoplasmic localization and high structural stability. CircCOL3A1 knockdown restored trophoblast migration, invasion, viability, and reduced apoptosis under hypoxia. Silencing circCOL3A1 suppressed hypoxia-induced ferroptosis by reducing ROS, MDA, and iron levels while restoring GSH and GPX4. Mechanistically, circCOL3A1 bound the RNA-binding protein TIAL1 to enhance p53 mRNA stability, thereby promoting p53-dependent ferroptosis. In vivo, circCOL3A1 silencing lowered maternal blood pressure and proteinuria, reduced placental ferroptosis, and improved fetal survival in PE rats. CircCOL3A1 drives trophoblast ferroptosis through a TIAL1-dependent stabilization of p53, contributing to PE progression. Targeting the circCOL3A1/TIAL1/p53 axis may offer a promising therapeutic strategy for preeclampsia.