Colorectal cancer (CRC) frequently metastasizes to the liver, which is the main driver of patient mortality. While circular RNAs (circRNAs) have emerged as critical regulators in cancer, their role in promoting CRC liver metastasis is still poorly understood. We examined circ-YAP expression using qRT-PCR and in situ hybridization, and assessed its impact on CRC cell proliferation, migration, and invasion through CCK-8, wound healing, and transwell assays. Mechanistic studies were performed using RNA immunoprecipitation, pull-down, luciferase reporter, and chromatin immunoprecipitation assays. The functional relevance of circ-YAP in liver metastasis was evaluated in a patient-derived xenograft (PDX) mouse model. Circ-YAP was markedly elevated in CRC tissues with liver metastasis and predicted worse clinical outcomes. Functionally, circ-YAP enhanced CRC cell motility in vitro and promoted hepatic colonization in vivo. Mechanistically, circ-YAP encodes a truncated 220-amino acid protein, YAP-220aa, which competes with LATS1, leading to YAP activation via dephosphorylation and nuclear translocation, thereby upregulating metastasis-related genes. Translation of circ-YAP is facilitated by m6A modification, mediated by YTHDF3 and the eIF4G2 initiation complex. Remarkably, circ-YAP transcription is reinforced by the YAP/TEAD complex, forming a self-amplifying positive feedback loop. Our study uncovers a novel circRNA-encoded oncoprotein that drives CRC liver metastasis and highlights circ-YAP as a potential prognostic biomarker and therapeutic target.
