Assessing the Prognostic and Therapeutic Value of Cuproptosis-Related Genes in Colon Adenocarcinoma Patients

Zhanhui Ye ¹ Yixian Song ¹ Mengqing Zhu ¹ Fuying Zheng ¹ Wenjie Qin ¹ Xue Li ¹ Pei Wang ² Zihua Li ^3* Kequan Chen ^4* Aimin Li ^1*

• ¹ Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
• ² Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ³ Tongji University, Shanghai, China
• ⁴ Guangzhou Medical University, Guangzhou, Guangdong Province, China

Background: Colon adenocarcinoma (COAD) remains a major global health challenge with poor prognosis despite advances in treatment, underscoring the need for new biomarkers. As a novel mode of cell death, cuproptosis is thought to be potentially involved in the development of cancer. However, theparticularly as the role of cuproptosis-related genes (CRGs) in COAD prognosis and therapy remains unclear.We analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) for COAD, focusing on CRG expression patterns and their clinicopathological correlations. Using the Weighted Gene Co-expression Network Analysis (WGCNA) method, we identified gene modules linked to cuproptosis and conducted functional enrichment analysis to explore their roles in COAD tumorigenesis. A novel prognostic risk model based on four CRGs (ORC1, PTTG1, DLAT, PDHB) was developed to stratify COAD patients into high-risk and low-risk groups, assessing overall survival, tumor microenvironment, and mutational landscape differences. We also evaluated the therapeutic effects of ferredoxin 1 (FDX1) and elesclomol on cuproptosis in HCT116 and LoVo cell lines through various experiments, including cell proliferation, apoptosis assessment, mitochondrial membrane potential evaluation, and DLAT lipoylation detection via Western blot.Results: Certain CRGs showed different expressions in COAD versus normal tissues.WGCNA identified a gene module linked to cuproptosis, crucial for pathways like cell cycle regulation, citrate cycle (TCA cycle), and DNA replication. The novel risk model stratified patients into high and low-risk groups based on risk scores, revealing that high-risk COAD patients had shorter overall survival and distinct immune cell infiltration, while low-risk patients were more sensitive to immunotherapy.Experimental results indicated that FDX1 exerted an inhibitory effect on COAD, and its combination with elesclomol significantly reduced proliferation, promoted apoptosis, increased DLAT lipoylation, and lowered mitochondrial membrane potential in COAD cells.The findings of this study provided a new perspective for the research on biomarkers and therapeutic strategies in COAD, evaluated the prognostic and therapeutic value of CRGs in COAD patients, and laid a theoretical foundation for the future clinical application of CRGs.