A multi-omics analysis of a succinylation-associated gene-expression signature in clear cell renal cell carcinoma: prognostic significance and the immune-metabolic microenvironment

Clear cell renal cell carcinoma (ccRCC) exhibits significant metabolic alterations. Protein succinylation, a metabolite-induced post-translational modification, plays a vital role in cellular metabolism and tumor biology.

To characterize the succinylation-associated transcriptional signature and its clinical relevance in ccRCC.

We developed a succinylation-associated transcriptional score based on a literature-curated 20-gene panel using the TCGA-KIRC RNA-seq dataset, with prognostic validation in two independent cohorts (E-MTAB-1980 and CPTAC). The tumor immune microenvironment was analyzed via ESTIMATE, CIBERSORT, and ssGSEA. Cellular localization of the score was investigated using single-cell and spatial transcriptomics. Functional enrichment, drug response analyses, and qPCR validation were also performed.

Tumor tissues demonstrated significantly reduced succinylation-associated transcriptional scores compared to normal counterparts, with higher scores correlating with improved clinical outcomes. Multivariate analyses supported the independent prognostic value of the succinylation-associated transcriptional score for overall survival in the TCGA and validation datasets. Interestingly, low-score tumors exhibited a transcriptionally “immune-hot” phenotype, characterized by enhanced immune cell infiltration and elevated immune checkpoint expression. Single-cell and spatial transcriptomic analyses suggested that tumor cells primarily contributed to the succinylation-associated transcriptional score. Functional assessments revealed that high scores were associated with oxidative phosphorylation and fatty acid metabolism, while low scores correlated with pro-tumorigenic signaling pathways. Computational drug sensitivity analysis identified exploratory associations that may inform future therapy stratification based on succinylation profiles.

The succinylation-associated transcriptional score represents a promising biomarker candidate in ccRCC, showing associations with prognosis and key metabolic-immune features. Our study underscores the role of succinylation in ccRCC biology and provides a framework for metabolic subtyping that may inform future biological and clinical stratification studies.