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已发表论文
循环丁酸盐通过EGFR和AMPK-Wip1信号减弱西妥昔单抗在结直肠癌中的疗效
Authors Zhang J, Zhang M , Wu X, Jing H, Li P, Wang W, Guo X, Zhao Z, Zhu S, Wang Y
Received 14 October 2025
Accepted for publication 15 January 2026
Published 22 January 2026 Volume 2026:20 574116
DOI https://doi.org/10.2147/DDDT.S574116
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Leonidas D. Panos
Jiayao Zhang,1– 3 Mingqing Zhang,1– 3 Xiaojing Wu,1,2 Haoren Jing,1– 3 Peiran Li,4 Wei Wang,5 Xi Guo,5 Zhenying Zhao,6 Siwei Zhu,1,2 Yijia Wang2
1School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 3Department of Colorectal Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 4Human Biology and Society, University of California, Los Angeles, CA, USA; 5TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, People’s Republic of China; 6Department of Pharmacy, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China
Correspondence: Siwei Zhu, School of Medicine, Nankai University, Tianjin, China; Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email siweiz@nankai.edu.cn Yijia Wang, Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email yijiawang_1980@nankai.edu.cn
Background: Cetuximab is an approved therapy for metastatic colorectal cancer (CRC) with wild-type RAS and BRAF; however, additional resistance mechanisms beyond genetic mutations remain poorly understood. Butyrate, a key metabolite produced by the gut microbiome and present in the circulatory system, has been reported to supply cellular energy and modulate the epidermal growth factor receptor (EGFR) downstream signaling pathway. However, whether butyrate affects the resistance to cetuximab is still unknown.
Methods: In this work, Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate the efficacy of cetuximab. Glycolysis/oxidative phosphorylation (OXPHOS) Assay Kit was applied to assess metabolic activity. Human Phospho-Kinase Array and RNA sequencing were employed to screen targets of butyrate. Overexpression plasmids and short hairpin RNAs (shRNAs) targeting these molecules were transfected into cells for further validation. Subcutaneous tumor and pulmonary metastasis models were used for in vivo studies.
Results: The findings showed that physiological concentrations of butyrate increased cetuximab resistance in KRAS wild-type cells only. Further investigation found that butyrate upregulated EGFR signaling through facilitating the binding reaction between epidermal growth factor (EGF) and EGFR. In parallel, butyrate activated AMP-activated protein kinase (AMPK)–wild-type p53-induced phosphatase 1 (Wip1) signaling, leading to suppression of p53 and p38 mitogen-activated protein kinase (p38 MAPK)-mediated pro-apoptotic signaling. These two mechanisms are the reason that butyrate attenuates the efficacy of cetuximab. Results of subcutaneous tumor and pulmonary metastasis models exhibited a similar conclusion to in vitro experiments.
Conclusion: Butyrate reduces cetuximab efficacy in KRAS wild-type colorectal cancer through EGFR and AMPK–Wip1 signaling, and may represent a candidate predictive biomarker for treatment response.
Keywords: cetuximab resistance, butyrate, colorectal cancer, EGFR signaling, AMPK/wip1 pathway
1School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 3Department of Colorectal Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 4Human Biology and Society, University of California, Los Angeles, CA, USA; 5TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, People’s Republic of China; 6Department of Pharmacy, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China
Correspondence: Siwei Zhu, School of Medicine, Nankai University, Tianjin, China; Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email siweiz@nankai.edu.cn Yijia Wang, Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email yijiawang_1980@nankai.edu.cn
Background: Cetuximab is an approved therapy for metastatic colorectal cancer (CRC) with wild-type RAS and BRAF; however, additional resistance mechanisms beyond genetic mutations remain poorly understood. Butyrate, a key metabolite produced by the gut microbiome and present in the circulatory system, has been reported to supply cellular energy and modulate the epidermal growth factor receptor (EGFR) downstream signaling pathway. However, whether butyrate affects the resistance to cetuximab is still unknown.
Methods: In this work, Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate the efficacy of cetuximab. Glycolysis/oxidative phosphorylation (OXPHOS) Assay Kit was applied to assess metabolic activity. Human Phospho-Kinase Array and RNA sequencing were employed to screen targets of butyrate. Overexpression plasmids and short hairpin RNAs (shRNAs) targeting these molecules were transfected into cells for further validation. Subcutaneous tumor and pulmonary metastasis models were used for in vivo studies.
Results: The findings showed that physiological concentrations of butyrate increased cetuximab resistance in KRAS wild-type cells only. Further investigation found that butyrate upregulated EGFR signaling through facilitating the binding reaction between epidermal growth factor (EGF) and EGFR. In parallel, butyrate activated AMP-activated protein kinase (AMPK)–wild-type p53-induced phosphatase 1 (Wip1) signaling, leading to suppression of p53 and p38 mitogen-activated protein kinase (p38 MAPK)-mediated pro-apoptotic signaling. These two mechanisms are the reason that butyrate attenuates the efficacy of cetuximab. Results of subcutaneous tumor and pulmonary metastasis models exhibited a similar conclusion to in vitro experiments.
Conclusion: Butyrate reduces cetuximab efficacy in KRAS wild-type colorectal cancer through EGFR and AMPK–Wip1 signaling, and may represent a candidate predictive biomarker for treatment response.
Keywords: cetuximab resistance, butyrate, colorectal cancer, EGFR signaling, AMPK/wip1 pathway