# Risk model of liquid–liquid phase separation‐related genes reveals the prognosis and tumor microenvironment characteristics of colorectal cancer

## TL;DR

A new risk model based on liquid-liquid phase separation genes helps predict colorectal cancer outcomes and treatment response.

## Contribution

The study introduces a novel LLPS-based risk model for CRC prognosis and tumor microenvironment analysis.

## Key findings

- High-risk patients have worse survival, higher tumor mutational burden, and reduced immune cell infiltration.
- Entinostat and 5-fluorouracil show potential therapeutic efficacy in high-risk CRC patients.
- Five LLPS-related genes are linked to epigenetic, splicing, and metabolic changes in CRC progression.

## Abstract

Colorectal cancer (CRC) progression involves liquid–liquid phase separation (LLPS), but its prognostic significance remains unexplored. Using The Cancer Genome Atlas transcriptomic data, we developed an LLPS‐based risk model that outperformed traditional clustering methods. High‐risk patients exhibited worse outcomes, correlating with higher tumor mutational burden and reduced natural killer/T‐cell infiltration, yet increased predicted response to immune checkpoint blockade. Drug sensitivity analysis suggested therapeutic efficacy of Entinostat and 5‐fluorouracil in this subgroup. Five pivotal genes (ASXL1, DDX21, HNRNPA1L2, TACC3, and TRIM28) were identified as LLPS‐driven regulators of CRC progression, mechanistically linking phase separation to epigenetic dysregulation, aberrant RNA splicing, and metabolic reprogramming. Our study provides the first LLPS‐associated prognostic framework for CRC, offering both a risk stratification tool and actionable therapeutic insights. The findings highlight LLPS as a critical molecular organizer in CRC pathogenesis and a potential target for precision oncology approaches.

A prognostic framework for colorectal cancer based on liquid–liquid phase separation (LLPS) genes stratifies patients by survival and tumor microenvironment. The pivotal gene signature—encompassing ASXL1, DDX21, HNRNPA1L2, TACC3, and TRIM28—is functionally linked to epigenetic and splicing dysregulation, providing independent risk assessment and therapeutic insights.