Honeybadger, a micropeptide encoded by an alternative PVT1 transcript, is a critical negative regulator of RAS–MAPK signaling in MYC-driven tumors

Genomic rearrangements can drive cancer through mechanisms that extend beyond classical oncogenic fusions such as BCR-ABL . A substantial fraction of these events involve long noncoding RNAs (lncRNAs), yet their functional impact on tumorigenesis has remained largely opaque. The lncRNA plasmacytoma variant translocation 1 ( PVT1 ), positioned adjacent to MYC at chromosome 8q24, is among the most frequently altered loci in MYC-driven (MYC + ) cancers. We recently showed that PVT1 translocations produce a characteristic asymmetric architecture that preserves the 5′- PVT1 region, generating a circular RNA ( CircPVT1 ) that encodes Firefox (FFX), a novel oncoprotein that activates AKT–mTORC1 signaling and cooperates with MYC. Here, we uncover a complementary and opposing function for the deleted 3′- PVT1 segment, which encodes a tumor-suppressive micropeptide we term Honeybadger (HNB). HNB binds KRAS and dampens RAS–MAPK signaling, and its loss derepresses this pathway and stabilizes MYC via Ser 62 phosphorylation. Thus, a single class of structural alterations at PVT1 simultaneously installs FFX-mediated AKT–mTORC1 activation and removes HNB-mediated RAS–MAPK regulation, creating a dual mechanism that synergistically amplifies MYC output. This oncoprotein gain coupled with tumor-suppressor loss provides a mechanistic explanation for the particularly poor prognosis of PVT1 -rearranged cancers and establishes PVT1 as a central regulatory hub in MYC + malignancies.