HNRNPC aggravates the symptoms of preeclampsia by regulating m6A-dependent alternative splicing of ACSL3

Background: Preeclampsia is a pregnancy-related disease causing significant maternal and perinatal morbidity and mortality, yet effective prevention and treatment are lacking. The role of heterogeneous nuclear ribonucleoprotein C (HNRNPC) in preeclampsia, as an alternative splicing factor and m 6 A reader, is unclear. Methods: We used RT-qPCR, western blot, and IHC to examine HNRNPC expression in preeclampsia placental tissues. CCK8, wound healing, and Transwell assays assessed HTR-8/SVneo cell functions. A mouse preeclampsia model was established to observe HNRNPC's in-vivo effects. RT-PCR, RT-qPCR, and western blot analyzed HNRNPC's regulation of acyl-CoA synthetase long chain family member 3 (ACSL3) alternative splicing. Co-IP, in-vitro ubiquitination assays, and western blot explored FBXW11-mediated HNRNPC ubiquitination. Results: HNRNPC was highly expressed in placental tissues of preeclampsia. In vitro , HNRNPC inhibited HTR-8/SVneo cell proliferation, migration, and invasion. HNRNPC knockdown in mice alleviated preeclampsia symptoms and caused dysregulation of the expression of ferroptosis markers. Mechanistically, HNRNPC bound to ACSL3 RNA, promoted exon 10 skipping. ACSL3 m 6 A site mutation reduced HNRNPC binding and ACSL3-S isoform. F-box and WD repeat domain containing 11 (FBXW11), as HNRNPC's E3 ubiquitin ligase, ubiquitinated and degraded HNRNPC, contributing to preeclampsia. Conclusion: Inhibiting HNRNPC altered the expression of ferroptosis-related markers and alleviated mouse preeclampsia symptoms, indicating HNRNPC as a potential preeclampsia therapeutic target.