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

Qiang Yuan, Yunshu Shi, Junyong Wang, Yifei Xie, Xiaoyu Li, Jimin Zhao, Yanan Jiang, Yan Qiao, Yaping Guo, Chengjuan Zhang, Jing Lu, Tongjin Zhao, Ziming Dong, Peng Li (), Zigang Dong () and Kangdong Liu ()
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Qiang Yuan: Zhengzhou University
Yunshu Shi: Zhengzhou University
Junyong Wang: Tianjian Laboratory for Advanced Biomedical Sciences
Yifei Xie: Zhengzhou University
Xiaoyu Li: Zhengzhou University
Jimin Zhao: Zhengzhou University
Yanan Jiang: Zhengzhou University
Yan Qiao: Zhengzhou University
Yaping Guo: Zhengzhou University
Chengjuan Zhang: The Affiliated Cancer Hospital of Zhengzhou University
Jing Lu: Zhengzhou University
Tongjin Zhao: Zhengzhou University
Ziming Dong: Zhengzhou University
Peng Li: Zhengzhou University
Zigang Dong: Zhengzhou University
Kangdong Liu: Zhengzhou University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58342-z

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