PHLDA2 in cancer: From molecular mechanisms to therapeutic opportunities

Pleckstrin homology-like domain, family A, member 2 (PHLDA2), an imprinted gene located on human chromosome 11p15.5, has emerged as a critical player in cancer biology with complex dual roles as both tumor suppressor and oncogene. This review synthesizes recent advances in understanding the mechanistic contributions of PHLDA2 to tumorigenesis, highlighting novel insights into its regulation of cellular processes, including apoptosis, autophagy, and ferroptosis, across diverse cancer types. We provide the first comprehensive comparative analysis of the context-dependent functions of PHLDA2, revealing how tumor microenvironment and cancer type determine its oncogenic versus tumor-suppressive roles. Key innovations addressed include the discovery of the role of PHLDA2 in ferroptosis through its interaction with ALOX12, its regulation of the PI3K/protein kinase B (AKT) pathway via competitive membrane binding, and its emerging potential as both a diagnostic biomarker and therapeutic target. The review critically examines current challenges in translating PHLDA2 research into clinical applications and identifies priority research directions for exploiting this protein's therapeutic potential in precision cancer medicine. SIGNIFICANCE STATEMENT: Pleckstrin homology-like domain, family A, member 2 functions as both oncogene and tumor suppressor across cancer types, regulating apoptosis, autophagy, and ferroptosis. Its dual roles and posttranslational modifications present novel opportunities for precision cancer diagnosis, prognosis, and targeted therapy development.