Work

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

Year: 2025

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202508515