RFC5 and STAT3 form a transcriptional complex to drive NSCLC progression via c-Myc.

Non-small cell lung cancer (NSCLC), a leading cause of cancer death worldwide, is often characterized by late diagnosis and treatment resistance, which adversely affect patient prognosis. This study identified replication factor C subunit 5 (RFC5) as a critical oncoprotein in NSCLC progression. Single-cell transcriptomic analysis of multi-stage NSCLC tissues revealed RFC5 as the most specific marker for a highly proliferative and migratory tumor subpopulation. RFC5 promoted NSCLC malignant phenotypes. Mechanistically, RFC5 interacted with and activated STAT3, functioning as a co-transcriptional activator to upregulate the expression of the oncogene c-Myc. Furthermore, GATA3 acts as an upstream negative regulator of RFC5. Collectively, this study revealed that RFC5 exerted a co-transcriptional activation function, which was negatively regulated by GATA3, to promote NSCLC progression by activating the STAT3-c-Myc signaling pathway. Thus, RFC5 represented a promising prognostic biomarker and therapeutic target for NSCLC.