The unique role of cuproptosis in the prognosis and treatment of rectum adenocarcinoma

Jun Ma; Huangwei Lin; Ying Wang; Yaming Zhang; Chaoping Zhou; Daibin Tang; Yoshinori Kagawa; Daorong Hou; Guoqin Jiang

doi:10.21037/jgo-2025-105

The unique role of cuproptosis in the prognosis and treatment of rectum adenocarcinoma

J Gastrointest Oncol. 2025 Apr 30;16(2):367-385. doi: 10.21037/jgo-2025-105. Epub 2025 Apr 1.

Authors

Jun Ma^#^{1

2}, Huangwei Lin^#³, Ying Wang⁴, Yaming Zhang², Chaoping Zhou², Daibin Tang², Yoshinori Kagawa⁵, Daorong Hou⁶, Guoqin Jiang¹

Affiliations

¹ Department of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
² Department of General Surgery, Anqing Municipal Hospital, Anqing, China.
³ Department of Surgery, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China.
⁴ Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, China.
⁵ Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.
⁶ Key Laboratory of Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing Medical University, Nanjing, China.

^# Contributed equally.

Abstract

Background: The incidence of digestive system cancers has increased significantly in recent years. Among these, rectum adenocarcinoma (READ), which exhibits distinct features compared to colon adenocarcinoma, has emerged as a unique subtype. Cuproptosis, a recently identified form of non-apoptotic programmed cell death, plays a pivotal role in tumorigenesis; however, its relationship with READ and its potential effect on prognosis remains poorly understood. This study innovatively explores the role of cuproptosis related genes (CRGs) in READ development and identifies potential therapeutic targets.

Methods: This study used consensus clustering to classify READ samples into three distinct clusters based on their survival status and enriched biological pathways. A cuproptosis-related score (CRS) was developed to examine the association between cuproptosis subtypes and patient prognosis. Immune infiltration was analyzed using multiple deconvolution algorithms to explore the immune landscape across different cuproptosis subtypes. A principal component analysis (PCA) was conducted to construct a prognostic score that reflects the clinical significance of cuproptosis in READ. Further investigations focused on lipoic acid synthetase (LIAS) as a key gene with prognostic implications for READ patients.

Results: Consensus clustering of the READ samples revealed three clusters with varying survival outcomes and distinct biological pathways. The CRS successfully predicted patient prognosis, and was found to be correlated with overall survival (OS) and tumor characteristics. The immune infiltration analysis revealed significant differences in immune profiles across the subtypes, with certain subtypes exhibiting immunosuppressive characteristics. LIAS was identified as a favorable prognostic marker for READ patients, and thus could serve as a potential therapeutic target.

Conclusions: CRGs play a critical role in the development and prognosis of READ. The established CRS could serve as a valuable tool for predicting patient outcomes. Further, LIAS emerged as a potential therapeutic target. Our findings may provide new avenues for targeted cancer treatment in READ.

Keywords: Cuproptosis; lipoic acid synthetase (LIAS); precision oncology; rectum adenocarcinoma (READ); tumor microenvironment (TME).