LZTS2 is a leucine zipper tumor suppressor that functions as a negative regulator of Wnt signaling and microtubule dynamics. At the molecular level, LZTS2 inhibits β-catenin-mediated transcription by promoting its nuclear exclusion and negatively regulates katanin-mediated microtubule severing, roles essential for cytokinesis completion and proper centrosomal function 1. Recent evidence reveals that LZTS2 is subject to complex post-translational regulation: its stability is bidirectionally controlled by the E3 ligase SPOP and deubiquitinase HAUSP in colorectal cancer 2, while in lung adenocarcinoma, PLK1-mediated phosphorylation at Ser451 disrupts LZTS2's ability to sequester β-catenin, activating Wnt signaling 3. In hepatocellular carcinoma, LZTS2 degradation via β-TrCP and CK1δ promotes PI3K/AKT activation, driving tumorigenesis and metastasis 4, and CCDC137-recruited β-TrCP similarly ubiquitinates LZTS2 to support HCC progression 5. LZTS2 also functions as a mechanosensitive effector of α-catenin required for cytokinetic fidelity; its depletion causes binucleation 6. High LZTS2 expression associates with poor overall survival in clear cell renal cell carcinoma 7. PLK1 inhibitors show promise for suppressing LUAD cell proliferation and migration in this pathway 3.