Disrupting the circTNC/miR-582-5p/MAPK8 axis alleviates oxidative stress-induced trophoblast dysfunction in preeclampsia.

Preeclampsia (PE) is a serious pregnancy complication characterized by hypertension and systemic inflammation, often driven by impaired trophoblast function and oxidative stress (OS). Circular RNAs (circRNAs) and microRNAs (miRNAs) are emerging regulators of placental development, yet the molecular interplay among circRNAs, miRNA maturation, and ferroptosis in PE remains unclear. This study aimed to elucidate the role of circTNC in promoting trophoblast ferroptosis and inflammation in PE through modulation of the miR-582-5p/MAPK8 signaling axis. Bioinformatics, in vitro, and in vivo approaches were used to elucidate the functional significance of the circTNC/miR-582-5p/MAPK8 axis in PE. HTR-8/SVneo trophoblasts were subjected to hypoxia/reoxygenation (H/R) injury to model ferroptosis, and a rat PE model was established via reduced uterine perfusion pressure. The effects of circTNC knockdown and ferrostatin-1 treatment were evaluated. Functional and mechanistic assays were conducted to assess interactions among circTNC, MAPK8, miR-582-5p, and DGCR8. CircTNC was upregulated in PE placentas, and its knockdown or ferroptosis inhibition ameliorated PE-like symptoms in rats, reducing OS, inflammation, and improving fetal outcomes. Mechanistically, circTNC suppressed MAPK8 expression by enhancing the DGCR8-mediated maturation of miR-582-5p. MiR-582-5p directly targeted MAPK8 and promoted trophoblast ferroptosis and inflammation. MAPK8 overexpression rescued trophoblast function and reversed the effects of circTNC. Furthermore, circTNC physically interacted with DGCR8 and facilitated the processing of pri-miR-582 into mature miR-582-5p. CircTNC promotes ferroptosis and inflammatory injury in PE by enhancing DGCR8-mediated miR-582-5p maturation and suppressing MAPK8 expression. These findings highlight the circTNC/miR-582-5p/MAPK8 axis as a novel regulatory pathway in PE pathogenesis.