Phase separation of circCHD6-encoded 216aa protein promotes colorectal cancer metastasis

Circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, yet their functional mechanisms remain largely unexplored. Here, we identify circCHD6-216aa, a protein encoded by the circRNA circCHD6, as a key driver of colorectal cancer (CRC) metastasis. CircCHD6-216aa forms nuclear condensates through liquid-liquid phase separation (LLPS) to function the pro-metastatic roles in CRC. Mechanistically, circCHD6-216aa promotes DExD/H-box helicase 9 (DHX9) phosphorylation to enhance upstream circCHD6 biogenesis, establishing a positive feedback loop. Additionally, circCHD6-216aa binds to nucleolin (NCL), stabilizing NCL's phase-separated condensates and promoting the transcription of CD44, a critical mediator of metastasis. These findings provide novel insights into the mechanistic roles of cancer-associated circRNA and reveal that a previously uncharacterized protein promotes cancer progression through LLPS.