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  3. Targeting 5-HT to Alleviate Dose-Limiting Neurotoxicity in Nab-Paclitaxel-Based Chemotherapy

Targeting 5-HT to Alleviate Dose-Limiting Neurotoxicity in Nab-Paclitaxel-Based Chemotherapy

  • Neurosci Bull. 2025 Jul;41(7):1229-1245. doi: 10.1007/s12264-025-01398-0.
Shuangyue Pan # 1 2,  Yu Cai # 1 2,  Ronghui Liu # 1 2,  Shuting Jiang # 1 2,  Hongyang Zhao # 1 2,  Jiahong Jiang 2,  Zhen Lin 2,  Qian Liu 2,  Hongrui Lu 2,  Shuhui Liang 2,  Weijiao Fan 2,  Xiaochen Chen 2,  Yejing Wu 2,  Fangqian Wang 3,  Zheling Chen 4,  Ronggui Hu 5 6 7,  Liu Yang 8 9
Affiliations

Affiliations

  • 1 Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China.
  • 2 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 3 Department of Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China. wfqzju@zju.edu.cn.
  • 4 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. chenzheling@hmc.edu.cn.
  • 5 Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China. coryhu00@gmail.com.
  • 6 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310000, China. coryhu00@gmail.com.
  • 7 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, 311121, China. coryhu00@gmail.com.
  • 8 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. yangliu@hmc.edu.cn.
  • 9 Zhejiang Provincial Clinical Research Center for Head and Neck Cancer, Zhejiang Key Laboratory of Precision Medicine Research on Head and Neck Cancer, Zhejiang Province Key Disciplines in Traditional Chinese Medicine-Integrated Traditional Chinese and Western Medicine Clinical Oncology, Hangzhou, 310014, China. yangliu@hmc.edu.cn.
  • # Contributed equally.
PMID: 40369268 DOI: 10.1007/s12264-025-01398-0
Abstract

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both Cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.

Keywords

Chemotherapy-induced peripheral neurotoxicity; Nab-paclitaxel; Serotonin; Venlafaxine.

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