Universität zu Köln

Ju, Feng, Weng, Jialei, Fan, Ningbo ORCID: 0000-0002-1622-6747, Wang, Zhefang ORCID: 0000-0002-2297-2586, Zhou, Chenghui ORCID: 0000-0003-1170-1761, Zhao, Xinlei, Horstmann, Nellie, Wu, Xiaolin ORCID: 0009-0006-3037-3328, Hoppe, Sascha, You, Bo ORCID: 0000-0002-3602-5264, Li, Keying, Duan, Jianxin, Odenthal, Margarete ORCID: 0000-0002-2424-0960, Hillmer, Axel M. ORCID: 0000-0002-3381-7266, Quaas, Alexander ORCID: 0000-0002-3537-6011, Bruns, Christiane J. ORCID: 0000-0001-6590-8181 and Zhao, Yue ORCID: 0000-0002-6790-3402 (2025). AKR1C3 enhances radioresistance in esophageal adenocarcinoma via inhibiting ferroptosis through suppressing TRIM21-mediated ubiquitination of HSPA5. Cell Death & Disease, 16 (1). pp. 1-16. Springer Nature. ISSN 2041-4889

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Abstract

[Artikel-Nr.: 483] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Ju, Feng UNSPECIFIED UNSPECIFIED UNSPECIFIED Weng, Jialei UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Ningbo UNSPECIFIED https://orcid.org/0000-0002-1622-6747 UNSPECIFIED Wang, Zhefang UNSPECIFIED https://orcid.org/0000-0002-2297-2586 UNSPECIFIED Zhou, Chenghui papamamaiuhui@163.com https://orcid.org/0000-0003-1170-1761 UNSPECIFIED Zhao, Xinlei UNSPECIFIED UNSPECIFIED UNSPECIFIED Horstmann, Nellie UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Xiaolin UNSPECIFIED https://orcid.org/0009-0006-3037-3328 UNSPECIFIED Hoppe, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED You, Bo UNSPECIFIED https://orcid.org/0000-0002-3602-5264 UNSPECIFIED Li, Keying UNSPECIFIED UNSPECIFIED UNSPECIFIED Duan, Jianxin UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED https://orcid.org/0000-0002-2424-0960 UNSPECIFIED Hillmer, Axel M. UNSPECIFIED https://orcid.org/0000-0002-3381-7266 UNSPECIFIED Quaas, Alexander UNSPECIFIED https://orcid.org/0000-0002-3537-6011 UNSPECIFIED Bruns, Christiane J. UNSPECIFIED https://orcid.org/0000-0001-6590-8181 UNSPECIFIED Zhao, Yue UNSPECIFIED https://orcid.org/0000-0002-6790-3402 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-801534
Identification Number:	10.1038/s41419-025-07773-z
Journal or Publication Title:	Cell Death & Disease
Volume:	16
Number:	1
Page Range:	pp. 1-16
Number of Pages:	16
Date:	2 July 2025
Publisher:	Springer Nature
ISSN:	2041-4889
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Chirurgie > Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Transplantationschirurgie
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80153