Potential role of PPARGC1A in linking ulcerative colitis to colorectal cancer: a novel prognostic biomarker and therapeutic target.

BACKGROUND

The rising incidence of ulcerative colitis (UC) worldwide significantly increases the risk of ulcerative colitis-associated colorectal cancer (UC-CRC). Although chronic inflammation drives the inflammation-dysplasia-carcinogenesis sequence, the early hit molecular factors remain poorly understood. This study aims to identify potential biomarkers and mechanisms from UC to UC-CRC.

METHODS

Multi-omics integration was performed using multiple database. We adopted an R-based workflow for differential expression analysis, functional enrichment analysis, and co-expression network analysis, gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Single-cell RNA sequencing verified cell-specific expression and perturbed genes by simulated knockout (KO) analysis. Clinical significance was evaluated by Kaplan-Meier and Cox regression analysis. Drug sensitivity was then predicted based on the Drug Sensitivity in Cancer (GDSC) database.

RESULTS

PPARGC1A was significantly downregulated in intestinal epithelial cells of both UC and colorectal cancer (CRC) patients. Its expression remained low throughout the malignant transformation process, serving as a possible early hit factor. Low expression was associated with poor overall survival (OS) and malignant phenotypes, such as EMT, mTORC1 signaling pathway, while high expression maintained metabolic homeostasis. Additionally, PPARGC1A deficiency was associated with an immunosuppressive microenvironment. Drug sensitivity analysis and molecular docking provides a theoretical basis for subsequent chemical optimization.

CONCLUSIONS

PPARGC1A may serve as potential early-hit factor for UC-CRC transformation. Suggesting the PPARGC1A axis represents a potential target for early warning and personalized management of patients at high risk of UC-CRC.