Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer

Hui Yang, Qingqing Li, Xingxing Chen, Mingzhe Weng, Yakai Huang, Qiwen Chen, Xiaocen Liu, Haoyu Huang, Yanhuizhi Feng, Hanyu Zhou, Mengying Zhang, Weiya Pei, Xueqin Li, Qingsheng Fu, Liangyu Zhu, Yingying Wang, Xiang Kong, Kun Lv (), Yan Zhang (), Yangbai Sun () and Mingzhe Ma ()
Additional contact information
Hui Yang: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Qingqing Li: Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation
Xingxing Chen: Fudan University Shanghai Cancer Center
Mingzhe Weng: Shanghai Jiaotong University
Yakai Huang: Fudan University Shanghai Cancer Center
Qiwen Chen: Fudan University Shanghai Cancer Center
Xiaocen Liu: Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation
Haoyu Huang: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Yanhuizhi Feng: Shanghai Engineering Research Center of Tooth Restoration and Regeneration
Hanyu Zhou: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Mengying Zhang: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Weiya Pei: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Xueqin Li: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Qingsheng Fu: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Liangyu Zhu: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Yingying Wang: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Xiang Kong: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Kun Lv: The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College)
Yan Zhang: Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation
Yangbai Sun: Fudan University Shanghai Cancer Center
Mingzhe Ma: Fudan University Shanghai Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.

Date: 2024
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DOI: 10.1038/s41467-024-48307-z

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