2. Academic Validation
  3. SNORA58 Facilitates Radioresistance via Suppressing JNK1-Mediated Ferroptosis in Esophageal Squamous Cell Carcinoma

SNORA58 Facilitates Radioresistance via Suppressing JNK1-Mediated Ferroptosis in Esophageal Squamous Cell Carcinoma

  • Adv Sci (Weinh). 2025 Jul 26:e08515. doi: 10.1002/advs.202508515.
Yinli Zheng 1 2,  Fangyi Liu 1 2,  Yuhua Huang 1 2,  Yanfen Feng 1 2,  Xia Yang 1 2,  Jinjun Wu 3,  Xin Yang 4,  Xuanhao Lin 5,  Lives Jiang 6,  Tingting Zeng 1,  Yan Li 1,  Xinyuan Guan 1 7 8,  Yuanyuan Wang 5,  Chunyan Chen 1 9,  Jingping Yun 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 3 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, P. R. China.
  • 4 Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518000, P. R. China.
  • 5 Department of Pathology, Shantou Central Hospital, Shantou, Guangdong, 515041, P. R. China.
  • 6 Department of Pathology, Affiliated Cancer Hospital and institute of Guangzhou Medical University, Guangdong, 510095, P. R. China.
  • 7 Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 852, P. R. China.
  • 8 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, P. R. China.
  • 9 Department of Radiology Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
PMID: 40714828 DOI: 10.1002/advs.202508515
Abstract

Radioresistance represents a substantial challenge in Cancer treatment, particularly in esophageal squamous cell carcinoma (ESCC), where the underlying molecular mechanisms remain incompletely understood. Small nucleolar RNAs (snoRNAs), primarily located in the nucleolus, are noncoding RNAs whose roles in ESCC radiotherapy are unclear. In this study, an upregulated snoRNA, SNORA58 is identified in ESCC via a snoRNA PCR array. Furthermore, based on multicenter data, SNORA58 is established as a promising biomarker for predicting response to neoadjuvant chemoradiotherapy (nCRT). Patients with high SNORA58 expression levels presented a lower likelihood of achieving a complete response to nCRT and poorer clinical outcomes. Functionally, SNORA58 enhances Cancer cell resistance to radiotherapy without affecting chemotherapeutic sensitivity. Mechanistically, SNORA58 stabilizes CTCF by inhibiting its ubiquitin-mediated degradation, leading to JNK1 downregulation and subsequent inactivation of the JNK signaling pathway; this disrupts intracellular iron homeostasis, thereby alleviating radiotherapy-induced Ferroptosis. Notably, the administration of a JNK signaling activator significantly restored the radiosensitivity of high-SNORA58 ESCC cells both in vitro and in vivo. These findings elucidate the first demonstration of SNORA58 as a critical regulator of radioresistance in ESCC and reveal a novel link between snoRNAs and Ferroptosis in this specific context, suggesting potential therapeutic strategies for managing ESCC.

Keywords

SNORA58; esophageal squamous cell carcinoma; ferroptosis, JNK1; radioresistance.

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