circRAB6A-encoded KAPEP relieves PTPN6-mediated restraint on JAK-STAT signaling to drive KRAS-mutant colorectal cancer progression

Despite advances in targeted therapy, effective treatment of KRAS-mutant colorectal cancer (CRC) remains challenging. Although circular RNAs (circRNAs) have emerged as important regulators of tumorigenesis, the functional significance of circRNA-encoded micropeptides in KRAS-mutant CRC remains poorly understood. Integrative transcriptomic profiling was used to identify dysregulated circRNAs in KRAS-mutant CRC. The coding potential of circRAB6A was evaluated using bioinformatic prediction, internal ribosome entry site (IRES) reporter assays, and mass spectrometry. The functional effects of circRAB6A and its encoded micropeptide were assessed using in vitro assays and orthotopic and patient-derived xenograft (PDX) models. Mechanistic studies combined RNA sequencing, co-immunoprecipitation, bio-layer interferometry, and molecular dynamics simulations. We identify circRAB6A as a highly expressed circRNA in KRAS-mutant CRC, with elevated circRAB6A abundance associated with poor clinical outcomes. circRAB6A harbors a short open reading frame and encodes a previously uncharacterized micropeptide, designated KAPEP. KAPEP promotes CRC cell proliferation, migration, and invasion in vitro and accelerates tumor growth in vivo. Mechanistically, KAPEP directly binds PTPN6 and inhibits its phosphatase activity, thereby relieving PTPN6-mediated restraint on JAK-STAT signaling and sustaining pathway activation. Our findings identify KAPEP as a functional circRNA-encoded micropeptide that promotes KRAS-mutant CRC progression through the PTPN6/JAK-STAT axis. These results highlight the KAPEP/PTPN6 interaction as a potential therapeutic vulnerability in KRAS-mutant CRC.