Porcupine (PORCN): structural insights, functional mechanisms, and therapeutic potential in Wnt-driven diseases

Porcupine (PORCN) is a membrane-bound O-acyltransferase primarily localized in the endoplasmic reticulum, where it catalyzes the palmitoylation of Wnt proteins-a critical post-translational modification required for their secretion and signal transduction. This lipid modification plays a key role in regulating essential cellular processes such as differentiation, proliferation, migration, and apoptosis. Inhibition of PORCN prevents Wnt palmitoylation, thereby blocking its extracellular transport and downstream signaling, including β-catenin production, which ultimately suppresses aberrant cell growth. While PORCN is a central regulator of the Wnt pathway, its involvement in disease pathogenesis-particularly in cancer-remains incompletely understood. This review summarizes current knowledge on PORCN's structural features, functional mechanisms, and its roles in both cancer and non-cancer diseases. We further highlight recent advances in the development of PORCN inhibitors as promising therapeutic agents, particularly for Wnt-driven cancers. Despite challenges in targeting this enzyme, PORCN remains a compelling candidate for therapeutic intervention in diseases associated with Wnt signaling dysregulation. This review also discusses ongoing challenges and emerging opportunities in PORCN-targeted drug discovery, aiming to provide insights that may guide future research and therapeutic development.