m6A-Modified circMELK Drives Nasopharyngeal Carcinoma Metastasis via a YTHDF1-HMGA2 Feedback Circuit

Abstract Background Circular RNAs (circRNAs) are emerging regulators in tumor biology. However, their roles in nasopharyngeal carcinoma (NPC) remain poorly defined. Methods By analyzing GSE190271, we identified hsa_circ_0138742 (circMELK) as significantly upregulated in NPC. Functional assays in vitro and in vivo were performed to explore its biological role. Mechanistic studies included RIP, ChIP, RNA pull-down, dual-luciferase assays, and rescue experiments. Results circMELK was markedly elevated in NPC tissues and cells. Silencing circMELK inhibited NPC cell proliferation, migration, and invasion, while overexpression enhanced these malignant traits. Mechanistically, m6A-modified circMELK is exported to the cytoplasm via YTHDF1. There, it acts as a ceRNA for miR-4775, relieving suppression of HMGA2. Elevated HMGA2 upregulates YTHDF1 by transcriptional activation, forming a circMELK/miR-4775/HMGA2/YTHDF1 positive feedback loop that drives epithelial–mesenchymal transition (EMT) and promotes metastasis. Conclusion circMELK promotes NPC progression via a novel m6A-dependent ceRNA regulatory loop. Targeting this axis may offer new therapeutic opportunities.