A competitive PDLIM1-USP14 axis destabilizes ACTN4 to disturb the invasive homeostasis of trophoblast in preeclampsia

Preeclampsia (PE) is characterized by insufficient extravillous trophoblast (EVT) invasion, but the cytoskeletal mechanisms restraining EVT motility remain unclear. TMT-based placental proteomics identified the cytoskeletal adaptor PDLIM1 as markedly upregulated in PE. In primary trophoblasts and cell lines, PDLIM1 depletion remodeled the actin cytoskeleton and enhanced migration and invasion, whereas trophoblast-restricted Pdlim1 overexpression impaired trophoblast invasion and placental development in mice. Mechanistically, PDLIM1 bounds the rod domain of α-actinin-4 (ACTN4) and competitively displaced USP14, limiting ACTN4 deubiquitination and shifting ACTN4 toward RNF38-associated K48-linked ubiquitination and proteasomal turnover. Importantly, placenta-targeted chondroitin sulfate A-binding nanoparticles delivering Pdlim1 short hairpin RNA (shRNA) alleviated PE-like maternal and fetal phenotypes in mice. Collectively, these findings define a PDLIM1-USP14-ACTN4 proteostatic axis controlling trophoblast invasive homeostasis and identify PDLIM1 as a potential therapeutic target in PE.