Abstract
Ferroptosis has increasingly emerged as a novel target for cancer therapy because of intrinsic or acquired ferroptosis vulnerabilities in cancers. Small nucleolar RNA (snoRNA)-mediated mRNA modifications play a critical role in regulating ferroptosis and supporting tumor cell adaptation. However, the function and mechanism of the box C/D snoRNA SNORD60 in hepatoblastoma (HB) remain poorly understood. Here, we found that SNORD60 expression was markedly downregulated in HB tissues, and restoring its expression inhibited HB cell proliferation and induced ferroptosis both in vitro and in vivo. Mechanistically, SNORD60 guided the 2′-O-methylation (Nm) of kielin/chordin-like protein (KCP) mRNA, and accelerated its degradation by resolving a G-quadruplex proximal to the Nm site. Furthermore, Silencing KCP induced lipid peroxidation and ferroptosis by suppressing ATF4-mediated transcription of SLC7A11. Moreover, plasma KCP protein levels were markedly higher in patients with HB than in healthy individuals, supporting KCP as a reliable non-invasive diagnostic biomarker for HB. High KCP expression correlates with poor patient prognosis. Overall, our findings reveal that SNORD60-mediated Nm modification of KCP prevents tumor cells from evading ferroptosis and inhibits tumor progression. This SNORD60/KCP axis represents a novel ferroptosis vulnerability and a promising therapeutic target in HB.
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This work is supported by the National Natural Science Foundation of China [NO: 82172357, 82293662, 82302615, 82302617, 82402711], Shanghai Leading Talent Program of Eastern Talent Plan, Leading Talents in Health Care of Shanghai Municipal Health Commission (2022LJ020), Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics (20dz2260900), Shanghai Municipal Health Commission Clinical Research Program of the Health Industry (20234Y0208), Sanya Science and Technology Special Fund (2022KJCX38), Clinical Research Program of Shanghai Municipal Health Commission (20234Y0208).
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The current study was approved by the Ethics Committee of Shanghai Children’s Medical Center, and written informed consent was obtained from each patient. The current study was performed in accordance with the Declaration of Helsinki. The animal experiments were performed with the approval of the Animal Ethics Committee of Shanghai Children’s Medical Center.
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Zhu, J., Ni, W., Bian, Z. et al. SNORD60-mediated 2′-O-methylation of KCP enhances ferroptosis sensitivity in hepatoblastoma. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03160-5
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DOI: https://doi.org/10.1038/s41420-026-03160-5
