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<p>Esophageal adenocarcinoma (EAC) is the predominant subtype of esophageal cancer (EC) in high-income countries, and radioresistance is one of the key factors for the poor prognosis. In this study, we successfully established a radioresistant EAC in vitro model. Aldo-keto reductase 1C3 (AKR1C3) was identified as a promising regulator of radioresistance by RNA-seq analysis and subsequent functional studies. Through integrated analyses of scRNA-seq and TCGA datasets, we found that AKR1C3 was likely to enhance radioresistance by inhibition of ferroptosis. Indeed, analysis of the lipid ROS level by C11-Bodipy staining and the result of transmission electron microscopy revealed that AKR1C3 could prevent EAC cells from ferroptosis. Mechanistically, AKR1C3 binds to the nucleotide-binding domain of HSPA5, thereby inhibiting the E3 ligase TRIM21-induced ubiquitin-dependent proteasomal degradation of HSPA5, which further stabilizes GPX4, thus inhibiting ferroptosis. Importantly, AKR1C3 inhibitor resensitized the EAC patient-derived organoids to radiotherapy. In conclusion, this study highlights AKR1C3 as a regulator of radioresistance and a potential therapeutic target in EAC.</p>

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AKR1C3 enhances radioresistance in esophageal adenocarcinoma via inhibiting ferroptosis through suppressing TRIM21-mediated ubiquitination of HSPA5

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • Feng Ju,
  • Jialei Weng,
  • Ningbo Fan,
  • Zhefang Wang,
  • Chenghui Zhou,
  • Xinlei Zhao,
  • Nellie Horstmann,
  • Xiaolin Wu,
  • Sascha Hoppe,
  • Bo You,
  • Keying Li,
  • Jianxin Duan,
  • Margarete Odenthal,
  • Axel M. Hillmer,
  • Alexander Quaas,
  • Christiane J. Bruns,
  • Yue Zhao

摘要

Esophageal adenocarcinoma (EAC) is the predominant subtype of esophageal cancer (EC) in high-income countries, and radioresistance is one of the key factors for the poor prognosis. In this study, we successfully established a radioresistant EAC in vitro model. Aldo-keto reductase 1C3 (AKR1C3) was identified as a promising regulator of radioresistance by RNA-seq analysis and subsequent functional studies. Through integrated analyses of scRNA-seq and TCGA datasets, we found that AKR1C3 was likely to enhance radioresistance by inhibition of ferroptosis. Indeed, analysis of the lipid ROS level by C11-Bodipy staining and the result of transmission electron microscopy revealed that AKR1C3 could prevent EAC cells from ferroptosis. Mechanistically, AKR1C3 binds to the nucleotide-binding domain of HSPA5, thereby inhibiting the E3 ligase TRIM21-induced ubiquitin-dependent proteasomal degradation of HSPA5, which further stabilizes GPX4, thus inhibiting ferroptosis. Importantly, AKR1C3 inhibitor resensitized the EAC patient-derived organoids to radiotherapy. In conclusion, this study highlights AKR1C3 as a regulator of radioresistance and a potential therapeutic target in EAC.