Comprehensive analysis identifies a lactylation-related signature for predicting prognosis and guiding therapies in colon adenocarcinoma.

Purpose: This study aimed to identify a lactylation-related gene signature for predicting prognosis and guiding therapies in colon adenocarcinoma (COAD). We seek to address the challenges in COAD prognostication due to tumor heterogeneity and variable treatment responses.

Methods: The study employed integrative bioinformatics analyses on multi-omics data from public databases, including gene expression profiles, clinical data, and lactylation-related genes (LRGs). The least absolute shrinkage and selection operator (LASSO) regression analysis and Cox risk model were applied to develop a prognostic signature. The predictive capabilities of the signature were assessed in four independent COAD cohorts (GSE39582, GSE71187, GSE75500, and GSE17536). Functional enrichment, immune infiltrations, and scRNA-seq analysis were performed to investigate biological processes and the tumor microenvironment (TME). Additionally, functional assays were performed to assess the impact of gene knockdown on COAD cell behavior.

Results: A 3-gene signature (SUSD5, FABP4, CALB2) was identified, demonstrating robust predictive performance for clinical outcomes in COAD patients across multiple cohorts. The signature revealed involvement in critical cancer-related biological processes and showed potential in guiding therapeutic decisions. The bulk RNA-seq and scRNA-seq analysis suggested that LRGs modulates the TME, particularly immune cell populations like mast cells. Knockdown of CALB2 significantly suppressed COAD cell proliferation, invasion, and migration.

Conclusion: This comprehensive analysis identified a lactylation-related signature with significant prognostic and therapeutic implications for COAD. The findings highlight the importance of lactylation in COAD biology and offer novel insights for developing personalized treatment strategies, potentially improving patient outcomes in this prevalent malignancy.