2. Academic Validation
  3. CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis

CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis

  • Oncogene. 2025 Mar 16. doi: 10.1038/s41388-025-03337-9.
Xiaoming Bai # 1,  Tinghong Duan # 1 2,  Jiaofang Shao # 3,  Yutong Zhang 1,  Guangyuan Xing 1,  Jie Wang 1,  Xue Liu 1,  Min Wang 1,  Yuanqiao He 4 5,  Hai Wang 2,  Zhi-Yuan Zhang 1,  Min Ni 6,  Jin-Yong Zhou 7 8,  Jinshun Pan 9
Affiliations

Affiliations

  • 1 Department of Pathology, Nanjing Medical University, Nanjing, PR China.
  • 2 Department of Pathology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China.
  • 3 Department of Bioinformatics, Nanjing Medical University, Nanjing, PR China.
  • 4 Center of Laboratory Animal Science, Nanchang University, Nanchang, PR China.
  • 5 Key Laboratory of New Drug Evaluation and Transformation of Jiangxi Province, Nanchang Royo Biotech Co., Ltd, Nanchang, PR China.
  • 6 Department of Colorectum, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, PR China. 13505157926@163.com.
  • 7 Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China. jinyongzhou@njucm.edu.cn.
  • 8 Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China. jinyongzhou@njucm.edu.cn.
  • 9 Department of Biotherapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, PR China. panjinshun@njmu.edu.cn.
  • # Contributed equally.
PMID: 40089640 DOI: 10.1038/s41388-025-03337-9
Abstract

Chemoresistance poses a significant challenge in colorectal Cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited Ferroptosis associated with multidrug resistance, and the Ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA Sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased Ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for Cancer treatment to overcome drug resistance in the future.

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