RPS6KA1 Remodels Fatty Acid Metabolism and Suppresses Malignant Progression in Colorectal Cancer

<b>Background</b>: Colorectal cancer (CRC), with high incidence but low rates of early diagnosis, poses significant challenges to public health worldwide. Lipid metabolic reprogramming has been closely associated with CRC occurrence and development. This study aimed to identify key fatty acid metabolism-related molecules involved in the development of CRC and to explore potential prognostic biomarkers and therapeutic targets. <b>Methods</b>: Based on The Cancer Genome Atlas (TCGA) data from colon adenocarcinoma (COAD) patients, we applied weighted gene co-expression network analysis (WGCNA), Cox regression, and least absolute shrinkage and selection operator (LASSO) to identify fatty acid metabolism-related signature genes in CRC. Expression validation and prognostic analysis were conducted. Summary-data-based Mendelian randomization (SMR) was used to infer causal relationships between target genes and CRC. Single-cell transcriptomics and immune infiltration analysis elucidated underlying pathogenic mechanisms. Cellular and animal experiments validated tumor-suppressive effects and lipid metabolic regulatory mechanisms. <b>Results</b>: RPS6KA1 and CHGA were identified as fatty acid metabolism-related signature genes in COAD. Only RPS6KA1 was significantly downregulated in COAD and negatively correlated with poor prognosis (<i>p</i> = 0.0069). SMR confirmed its tumor-suppressive role, potentially associated with enhanced antitumor functions of CD8⁺T cells and follicular helper T cells. In vitro and in vivo experiments demonstrated that RPS6KA1 inhibits malignant progression of colon cancer and modulates fatty acid metabolism. <b>Conclusions</b>: Integrated multi-dimensional bioinformatic and experimental analyses reveal that RPS6KA1 remodels fatty acid metabolism and suppresses malignant progression, indicating its value as a prognostic biomarker in CRC and providing new insights for therapeutic strategies.