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Immunol."],"abstract":"<jats:p>This study investigates the role of ubiquitination-related genes in pancreatic cancer (PC) using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multi-omics approaches. scRNA-seq data (GSE155698) from PC samples identified 12 cell types, with endothelial cells exhibiting high ubiquitination scores (High_ubiquitin-Endo) and enriched interactions with fibroblasts\/macrophages via WNT, NOTCH, and integrin pathways. Spatial transcriptomics (GSE235315) validated cell-type localization. Mendelian randomization (SMR) analysis prioritized TRIM9 as a PC-protective gene, downregulated in tumors and correlated with better survival. WGCNA revealed TRIM9-co-expressed modules linked to prognosis. A machine learning-based prognostic model (CoxBoost+RSF) integrating seven genes (TSPAN6, TSC1, RNF167, PBXIP1, LRRC49, KATNAL2, IGF2BP2) stratified patients into high\/low-risk groups with distinct survival, mutation burdens, and immune infiltration. TRIM9 overexpression suppressed PC cell proliferation\/migration <jats:italic>in vitro<\/jats:italic>, while knockdown enhanced malignancy. Mechanistically, TRIM9 promoted K11-linked ubiquitination and proteasomal degradation of HNRNPU, dependent on its RING domain. <jats:italic>In vivo<\/jats:italic>, TRIM9 overexpression reduced tumor growth, rescued by HNRNPU co-expression. Integrated analyses highlight TRIM9 as a tumor suppressor and prognostic biomarker, mediated via ubiquitination-dependent regulation of HNRNPU stability. This work provides insights into ubiquitination-driven PC pathogenesis and therapeutic targeting.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1631708","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T05:31:40Z","timestamp":1758259900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Single-cell and multi-omics analysis identifies TRIM9 as a key ubiquitination regulator in pancreatic 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