Work

Single-cell profiling reveals GABBR1 as a cuproptosis-regulated prognostic biomarker in pancreatic cancer

Year: 2026

Type: article

Abstract: Background and aims Cuproptosis is a recently identified copper-dependent form of cell death with potential therapeutic applications. However, its activity in cancer-associated fibroblasts (CAFs) and its association with pancreatic cancer (PC) prognosis remain poorly understood. This study aimed to address this gap. Methods We performed integrated analyses of scRNA-seq data from patients with PC (GSE212966) and The Cancer Genome Atlas-pancreatic adenocarcinoma dataset. Based on cuproptosis-related AUCell scores, fibroblasts were stratified into high-score (cuproptosis-high) and low-score (cuproptosis-low) groups. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with cuproptosis-related genes (CRGs), followed by random survival forest modeling to screen prognostic genes. Functional assessments included gene set variation analysis, immune infiltration analysis via CIBERSORT, and immunohistochemistry for experimental validation. Results scRNA-seq analysis identified fibroblasts as the principal cell type with elevated cuproptosis activity. By integrating WGCNA with survival analysis, we identified GABBR1 as a key gene whose expression decreased with increase in tumor progression. Fibroblasts expressing higher GABBR1 levels also exhibited increased expression of immune checkpoint genes and T-cell activation markers. A nomogram integrating GABBR1 expression with clinical features showed strong prognostic performance. Immunohistochemical validation confirmed that GABBR1 , LIAS , and LIPT1 were expressed at significantly lower levels in tumor tissues than in adjacent normal tissues. Importantly, GABBR1 expression negatively correlated with PC progression and was linked to CRGs ( LIAS and LIPT1 ), emerging as a novel CAF-specific biomarker. Conclusion Modulating GABBR1 can reshape cuproptosis pathways, thereby influencing apoptotic sensitivity and modulating immune responses.

Source: iLiver

DOI: 10.1016/j.iliver.2026.100276