2. Academic Validation
  3. p38 mediated ACSL4 phosphorylation drives stress-induced esophageal squamous cell carcinoma growth through Src myristoylation

p38 mediated ACSL4 phosphorylation drives stress-induced esophageal squamous cell carcinoma growth through Src myristoylation

  • Nat Commun. 2025 Apr 7;16(1):3319. doi: 10.1038/s41467-025-58342-z.
Qiang Yuan 1 2 3 4,  Yunshu Shi 1 2 3 4,  Junyong Wang 3,  Yifei Xie 1,  Xiaoyu Li 1 2 3 4,  Jimin Zhao 1 5 6,  Yanan Jiang 1 5 6,  Yan Qiao 1 5 6,  Yaping Guo 1 5 6,  Chengjuan Zhang 7,  Jing Lu 1 5 6,  Tongjin Zhao 1 3 8,  Ziming Dong 1 5 6,  Peng Li 9 10 11,  Zigang Dong 12 13,  Kangdong Liu 14 15 16 17 18
Affiliations

Affiliations

  • 1 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 2 State Key Laboratory of Metabolic dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, China.
  • 3 Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan, China.
  • 4 China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
  • 5 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China.
  • 6 Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
  • 7 Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
  • 8 State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai Qi Zhi Institute, Shanghai, China.
  • 9 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. li-peng@mail.tsinghua.edu.cn.
  • 10 State Key Laboratory of Metabolic dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, China. li-peng@mail.tsinghua.edu.cn.
  • 11 Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan, China. li-peng@mail.tsinghua.edu.cn.
  • 12 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. zgdong@hci-cn.org.
  • 13 Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan, China. zgdong@hci-cn.org.
  • 14 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. kdliu@zzu.edu.cn.
  • 15 State Key Laboratory of Metabolic dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, China. kdliu@zzu.edu.cn.
  • 16 Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, Henan, China. kdliu@zzu.edu.cn.
  • 17 China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China. kdliu@zzu.edu.cn.
  • 18 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China. kdliu@zzu.edu.cn.
PMID: 40195298 DOI: 10.1038/s41467-025-58342-z
Abstract

The comprehension of intricate molecular mechanisms underlying how external stimuli promote malignancy is conducive to Cancer early prevention. Esophageal squamous cell carcinoma (ESCC) is considered as an external stimuli (hot foods, tobacco, chemo-compounds) induced Cancer, characterized by stepwise progression from hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma. However, the underlying molecular mechanism governing the transition from normal epithelium to neoplastic processes in ESCC under persistent external stimuli has remained elusive. Herein, we show that a positive correlation between p38 and ERK1/2 activation during the progression of ESCC. We identify that phosphorylation of ACSL4 at T679 by p38 enhances its enzymatic activity, resulting in increased production of myristoyl-CoA (C14:0 CoA). This subsequently promotes Src myristoylation and activates downstream ERK signaling. Our results partially elucidate the role of ACSL4 in mediating stress-induced signaling pathways that activate growth cascades and contribute to tumorigenesis.

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