SNORD60-mediated 2′-O-methylation of KCP enhances ferroptosis sensitivity in hepatoblastoma

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.