2. Academic Validation
  3. Nociceptive neurons protect cancer cells against oxidative stress

Nociceptive neurons protect cancer cells against oxidative stress

  • Cell Rep. 2026 Mar 24;45(3):117086. doi: 10.1016/j.celrep.2026.117086.
Yu Zhang 1,  Mingtao Chen 2,  Xiaohu Lin 3,  Weijie Zhuang 2,  Zheqi Liu 2,  Yibo Guo 1,  Guanying Feng 2,  Zhen Zhang 2,  Yun Zhu 2,  Jinhai Ye 2,  Tong Ji 2,  Yang Wang 4,  Minjiao Wang 5,  Wei Cao 6,  Chengzhong Lin 7
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China; Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 3 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
  • 4 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 5 Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China. Electronic address: [email protected].
  • 6 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China. Electronic address: [email protected].
  • 7 Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 41831232 DOI: 10.1016/j.celrep.2026.117086
Abstract

How Cancer cells exploit the tumor microenvironment (TME) to alleviate oxidative stress remains largely unclear. Here, we show that nociceptive neurons, via secretion of Epiregulin, increase Lnc-GCLC-1 expression in Cancer cells, thereby protecting them against oxidative stress-induced cell death in head and neck squamous cell carcinoma (HNSCC). Specifically, nociceptive neurons increase Ets variant 4 (ETV4)-mediated Lnc-GCLC-1 expression in Cancer cells upon oxidative stress. Increased cellular Lnc-GCLC-1 interacts with and ubiquitinates Kelch-like ECH-associated protein 1 (KEAP1), leading to disruption of the Keap1-Nrf2 interaction and subsequent activation of the NRF2 signaling pathway. This enhances GSH biosynthesis in Cancer cells and protects them against cisplatin-induced oxidative stress. Targeting nociceptive neurons or the EREG-Lnc-GCLC-1-NRF2 axis therefore improves the therapeutic efficacy of cisplatin. Moreover, high Lnc-GCLC-1 levels correlate with poor prognosis in patients with HNSCC. Our study sheds light on nociceptive neurons as accomplices that assist HNSCC cells in surviving oxidative stress.

Keywords

CP: cancer; CP: neuroscience; NRF2; cancer neuroscience; cell death; chemotherapy; cisplatin; head and neck squamous cell carcinoma; long-noncoding RNA; nociceptive neurons; oxidative stress; tumor microenvironment.

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