Clinofibrate Disrupts the SNORA80B/YTHDC1‐Driven M6A Modification to Suppress Cholesterol Metabolism and Cisplatin Resistance in ESCC

Esophageal squamous cell carcinoma (ESCC) progression is driven by androgen receptor (AR) signaling, while small nucleolar RNAs (snoRNAs), classically involved in ribosomal RNA processing, are increasingly recognized for non-classical roles in cancer. However, their function in ESCC remains unknown. This study investigates AR-regulated snoRNAs and their mechanistic contributions to ESCC pathogenesis. SNORA80B is identified as the most AR-responsive snoRNA with oncogenic activity by transcriptomic profiling. Beyond its classical role, SNORA80B stabilizes cholesterol metabolism transcripts via N⁶-methyladenosine (m⁶A)-YTHDC1, driving cholesterol/DHT accumulation and lipid droplets (LDs) formation. A feedforward loop is observed wherein DHT-activated AR upregulates SNORA80B, which further enhances AR signaling through cholesterol metabolic reprogramming. Clinofibrate, identified as a SNORA80B inhibitor through high-throughput screening of FDA-approved drugs, disrupts this axis and demonstrates synergistic effects with cisplatin, overcoming resistance in ESCC. The study reveals a novel non-classical function of SNORA80B in ESCC, establishing it as a key effector of AR-driven metabolic reprogramming through m⁶A-dependent regulation. The repurposing of clinofibrate demonstrates the therapeutic potential of targeting snoRNA-mediated pathways, providing both mechanistic insights and a clinically translatable strategy for ESCC treatment. These findings redefine the functional scope of snoRNAs in cancer pathogenesis.