# Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1

## TL;DR

This study explores the role of the unfolded protein response in prostate cancer and identifies IFRD1 as a key gene linked to tumor progression and poor outcomes.

## Contribution

The study provides the first systematic single-cell atlas of UPR heterogeneity in prostate cancer and introduces a clinically translatable UPR-related prognostic signature.

## Key findings

- A seven-UPRRG signature, including IFRD1, showed strong prognostic performance across multiple cohorts.
- UPRRS was confirmed as an independent prognostic factor beyond clinical stage and Gleason score.
- IFRD1 knock-down reduced prostate cancer cell proliferation and migration in vitro.

## Abstract

The unfolded protein response (UPR) promotes prostate cancer (PCa) progression, yet its multi-omics landscape and clinical utility remain undefined.

We integrated single-cell and bulk transcriptomic datasets, and identified UPR-related genes (UPRRGs) through a combination of differential expression analysis and weighted gene co-expression network analysis (WGCNA), based on which we further developed a consensus UPR-related signature (UPRRS) using a machine learning framework. The UPRRGs were further characterized by functional enrichment, cell-cell communication, and survival analyses. A clinically applicable nomogram integrating UPR-related prognostic genes was constructed for prognostic prediction. Through in silico and in vitro analyses, we validated the clinical relevance between the hub UPRRGs and PCa progression.

Single-cell analyses revealed elevated UPR activity in prostate epithelial cells, most prominently within the LE-KLK3 subpopulation. These cells exhibited enhanced ligand–receptor interactions in TNF, VEGF and NOTCH signaling axes. A seven-UPRRG signature (including IFRD1, DDIT3, HSPA5) demonstrated robust prognostic performance in the TCGA training set and three external validation cohorts (C-index > 0.82; AUC > 0.80). Multivariate Cox analysis confirmed UPRRS as an independent prognostic factor beyond clinical stage and Gleason score. Mechanistically, the UPRRS-high subgroup displayed an immunosuppressive microenvironment and reduced sensitivity to multiple chemotherapeutics. In vitro knock-down of IFRD1 markedly attenuated PCa cell proliferation and migration.

We provide the first systematic single-cell atlas of UPR heterogeneity in PCa and develop a clinically translatable UPRRS prognostic model. IFRD1, a key driver, emerges as a dual diagnostic and therapeutic target, offering both theoretical and experimental foundations for precision stratification and individualized management of PCa.

Flowchart illustrating the study of UPR in prostate cancer. It details the discovery and validation cohorts for RNA sequencing, identification of UPR signature, and development of the UPRRS model using methods like Random Forest and COX+LASSO. The chart shows clinical correlations of IFRD1 with prostate cancer progression and poor prognosis. Includes tools like AUCell, scMETABOLISM, WGCNA, and TIME, highlighting diagnostic, prognostic, and clinical evaluation processes through survival analysis, clinicalpathology, and molecular mechanisms.