EMT Dysfunction in Renal Primitive Vesicle Cells Drives Poor Prognosis in Wilms' Tumor via hnRNP A1 and PARP1-Mediated TGF-β/NF-κB Signaling

Wilms' tumor (WT), a common pediatric renal malignancy, exhibits high histological heterogeneity and variable prognosis. The role of epithelial-mesenchymal transition (EMT) dysfunction in primitive renal progenitor cells in unfavorable WT remains unclear. Here, integrative single-cell RNA sequencing, bulk transcriptomics, and SWATH-MS proteomics analyses identified renal primitive vesicle (PV) cells with active EMT signatures as key contributors to unfavorable WT, linked to dedifferentiation and poor survival. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and poly(ADP-ribose) polymerase 1 (PARP1) were highly expressed in PV cells, activating TGF-β/NF-κB signaling, promoting necroptosis-related inflammation, and maintaining PV cell dedifferentiation. High hnRNP A1 and PARP1 expression independently predicted poor WT prognosis, validated by survival analyses and nomogram modeling. Our findings reveal that hnRNP A1/PARP1-mediated EMT dysfunction in PV cells drives unfavorable WT biology, offering novel biomarkers and potential therapeutic targets for high-risk WT.