LZTS2 (leucine zipper tumor suppressor 2) functions as a multifaceted tumor suppressor through its regulation of the Wnt signaling pathway and centrosomal microtubule dynamics. Primary Function: LZTS2 negatively regulates β-catenin-mediated transcriptional activation by promoting its nuclear exclusion, thereby suppressing the canonical Wnt pathway 123. Additionally, LZTS2 localizes to centrosomes where it negatively regulates CEP135 levels and centrosomal microtubule nucleation 4, and functions as a mechanosensitive effector of α-catenin critical for proper cytokinesis completion 5. Mechanism: LZTS2 stability is controlled by competing ubiquitination and deubiquitination: SPOP and β-TrCP promote LZTS2 degradation via K48-linked polyubiquitination, while HAUSP counteracts this through deubiquitination 26. PLK1-mediated phosphorylation at Ser451 disrupts LZTS2-β-catenin interaction without affecting LZTS2 levels 3. Disease Relevance: LZTS2 downregulation correlates with poor prognosis in hepatocellular carcinoma, colorectal cancer, lung adenocarcinoma, and lung squamous cell carcinoma 12738. Clinical Significance: Peptides disrupting CCDC137-LZTS2 interaction show efficacy in inhibiting HCC progression in organoids and PDX models 1, positioning LZTS2-targeting strategies as promising therapeutic approaches.