Transferrin receptor 1 (TfR1), a widely expressed type II transmembrane glycoprotein located on the plasma membrane, is well known for its established role in cellular iron uptake. Nevertheless, emerging evidence implies that TfR1 exhibits previously unrecognized noncanonical functions. Herein, we demonstrated the nuclear translocation of TfR1 and revealed the interaction between TfR1 and p53 within the nucleus. Through comprehensive analyses at the proteomic, genomic, and transcriptomic levels, we demonstrated that this interaction significantly influences the transcriptional activity of p53 on its downstream target genes, which are highly enriched in DNA damage repair functions. Specifically, our investigation revealed the indispensable role of nuclear TfR1 in the regulation of the nucleotide excision repair (NER) pathway, exemplified by the transcriptional regulation of XPC. Notably, both in vitro and in vivo results revealed a positive regulatory role of TfR1 in the NER pathway. Subsequent phenomic analysis of clinical colorectal tumor samples confirmed a positive correlation between nuclear TfR1 levels and tumor malignancy, aggressive features, and metastasis. Collectively, our findings highlight the non-classical function of TfR1, emphasizing its importance in the regulation of gene expression, as well as tumor progression.
© 2025. The Author(s).