LLPS-based classification and a novel prognostic signature reveal NRF1 as a therapeutic target in pancreatic cancer.

Authors

Weishen Wang, Yi Zhao, Songyao Jiang, Yiwei Zhou, Qinxin Yang, Dan Li, Yu Jiang, Haoda Chen, Xiaomei Tang, Linjie Ren, Jia Liu, Jiabin Jin, Da Fu, Hong Yu

Published in

Cancer cell international. Jun 26, 2026. Epub Jun 26, 2026.

Abstract

Aberrant liquid-liquid phase separation (LLPS) can alter biomolecular condensate functions and may influence pancreatic tumorigenesis and progression, but the specific role of LLPS regulators in prognosis and the tumor immune microenvironment (TIME) in pancreatic ductal adenocarcinoma (PDAC) remains unclear.
We integrated transcriptome data of LLPS regulator-related differentially expressed genes (DEGs; n = 298) in a cohort of 176 PDAC patients from TCGA. Three LLPS regulator subtypes (LS1-LS3) were identified through multi-omics analyses, and a prognostic LLPS subtype-related risk model (LRRPC) was developed and validated. Chromatin immunoprecipitation confirmed NRF1 binding to promoters of key risk genes, and in vitro and in vivo experiments assessed the effects of NRF1 targeting on tumor growth.
The three LLPS regulator subtypes exhibited significant differences in prognosis, clinical features, genomic alterations, TIME patterns and predicted immunotherapy response. The LRRPC signature predicted prognosis and immunotherapy efficacy across cohorts and was associated with tumor biomarkers and immune infiltration. Nuclear Respiratory Factor 1 (NRF1) directly regulated hub genes such as FAM83A, RHOV and ITGB6, promoting PDAC cell proliferation, while its inhibition induced apoptosis and reduced tumor growth.
This study proposes an LLPS-based stratification framework for PDAC, and the LRRPC model provides an LLPS subtype-related risk score that may assist personalized prognostic assessment and immunotherapy stratification. NRF1 emerges as a promising therapeutic candidate whose targeting can inhibit tumor progression in PDAC experimental models and warrants further evaluation.

PMID:
42363116
Bibliographic data and abstract were imported from PubMed on 27 Jun 2026.

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