NOP2-mediated 5-methylcytosine Regulates Lipid Metabolism Reprogramming to Prime Tumors for Ferroptosis in Bladder Cancer Progression.

RNA 5-methylcytosine (m5C) is an emerging epitranscriptomic modification implicated in the progression of multiple cancers, yet the landscape of m5C in bladder cancer (BCa) and underlying regulatory mechanisms remains largely elusive. In this study, we identified NOP2, an RNA methyltransferase, as a key driver of BCa progression. NOP2 was significantly upregulated in BCa tumors and associated with poor prognosis. Functionally, NOP2 promoted cell proliferation and invasion, enhancing tumor growth in xenograft models. Mechanistically, NOP2-mediated m5C deposition facilitates the recruitment of the m5C reader YBX1, thereby stabilizing SCD mRNA and boosting SCD expression. The NOP2/SCD axis orchestrated lipid metabolism reprogramming, altering the distribution of saturated, monounsaturated, and polyunsaturated fatty acids to suppress lipid peroxidation and protect BCa cells from ferroptotic stress. Collectively, our findings determine the oncogenic role of the m5C methyltransferase NOP2 in BCa and reveal a novel NOP2/YBX1/SCD axis that links epitranscriptomic regulation, metabolic reprogramming and ferroptosis evasion, providing a new target for therapeutic intervention.