{"id":359,"title":"A competitive PDLIM1-USP14 axis destabilizes ACTN4 to disturb the invasive homeostasis of trophoblast in preeclampsia","title_zh":"竞争性 PDLIM1-USP14 轴通过去稳定 ACTN4 扰乱子痫前期滋养细胞侵袭稳态","url":"https://pubmed.ncbi.nlm.nih.gov/42965865","doi":"10.1016/j.celrep.2026.118211","pmid":"42965865","journal":"Cell Rep","kind":"paper","lang":"en","published_at":"2026-10-30T00:00:00+00:00","fetched_at":"2026-11-08T03:44:12+00:00","authors":["Zhang C","Zhang X","Chen R","Xiang Y","Gong E","Tong H","Sun X","Yin H","Qi H"],"primary_topic":"endometrium","topics":[{"slug":"endometrium","score":7.0,"hits":["placenta","placental","trophoblast","trophoblast invasion"]},{"slug":"early-pregnancy","score":4.0,"hits":["preeclampsia"]},{"slug":"omics-methods","score":1.0,"hits":["proteomics"]}],"topic_score":7.0,"preference_score":0.0,"preference_labels":[],"llm_score":78.0,"final_score":86.0,"score_dims":{"novelty":82,"rigor":80,"impact":72,"relevance":62,"translation":65},"recommend_reason":"首次提出 PDLIM1-USP14-ACTN4 蛋白稳态轴调控滋养细胞侵袭，并有胎盘靶向纳米颗粒干预的体内验证，机制链条完整；对理解子痫前期胎盘病理与早期胎盘形成有参考价值，但属产科病理而非 ART 核心环节。","keywords":["子痫前期","滋养细胞侵袭","PDLIM1","ACTN4","泛素化","胎盘靶向纳米递送"],"selected":1,"story_id":265,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"cell-rep","journal_tier":"cns-sub","journal_if":7.5,"is_mock":false,"summary_zh":"本研究针对子痫前期（PE）中绒毛外滋养细胞（EVT）侵袭不足的细胞骨架机制展开。基于 TMT 胎盘蛋白质组学，研究者发现细胞骨架衔接蛋白 PDLIM1 在 PE 胎盘中显著上调；在原代滋养细胞与细胞系中敲低 PDLIM1 可重塑肌动蛋白骨架并增强迁移侵袭，而小鼠滋养细胞特异性过表达 Pdlim1 则损害侵袭与胎盘发育。机制上，PDLIM1 结合 α-actinin-4（ACTN4）杆状结构域并竞争置换 USP14，减少 ACTN4 去泛素化，使其转向 RNF38 介导的 K48 连接泛素化与蛋白酶体降解。胎盘靶向的硫酸软骨素 A 结合纳米颗粒递送 Pdlim1 shRNA 可缓解小鼠 PE 样母胎表型，提示 PDLIM1 为潜在治疗靶点。","summary":"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.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}