Integrating spatial and single-cell transcriptomics analysis reveals MYCN-UBE2C-TFRC signaling endows ferroptosis resistance in neuroectodermal tumors.

MYCN amplification is a recurrent, high-risk molecular hallmark across diverse tumors, most notably neuroectodermal malignancies. Although MYCN-driven tumors uniformly exhibit robust intrinsic resistance to ferroptosis, the mechanistic link between MYCN and the ferroptotic pathway remains undefined. Here, we charted the genomic and epigenomic landscape of neuroectodermal tumors by combining single-cell RNA-seq, spatial transcriptomics (ST), CUT&Tag, and deep-coverage mass spectrometry proteomics. This integrative atlas identified UBE2C as a spatially resolved, MYCN-controlled driver gene. MYCN occupies the UBE2C promoter and potently transactivates its transcription, thereby accelerating tumor progression in vitro and in vivo. Re-expression of UBE2C fully rescued the proliferative arrest triggered by MYCN depletion, confirming its essential function downstream of MYCN. Proteomic interrogation of the UBE2C interactome further revealed that the tumor suppressor TFRC is a previously unknown ubiquitination substrate of UBE2C. Mechanistically, the polyubiquitination and proteasomal degradation of TFRC by UBE2C reduces iron influx and effectively shields cancer cells from ferroptosis. Clinically, genetic silencing of UBE2C induces ferroptosis and sensitizes tumor cells to the ferroptosis inducer erastin, revealing a therapeutically exploitable vulnerability in MYCN-amplified malignancies. Our study reveals a previously unrecognized MYCN-UBE2C-TFRC-ferroptosis regulatory axis that drives neuroectodermal tumor growth. These findings establish a mechanistic rationale for combining UBE2C silencing and ferroptosis induction as a precision therapeutic strategy against MYCN-amplified tumors.