The deubiquitinating enzyme USP42 promotes lung adenocarcinoma progression through PTGS2

The ubiquitin-specific peptidase 42 (USP42) is a cysteine-dependent deubiquitinase with pro-tumorigenic roles in several cancers. In lung adenocarcinoma (LUAD), elevated USP42 expression correlates with advanced stage and poor survival, mirroring the prognostic impact of prostaglandin-endoperoxide synthase 2 (PTGS2) overexpression. However, the substrate repertoire and mechanisms by which USP42 drives malignant progression and immune evasion in LUAD remain largely undefined. Using TCGA datasets and functional experiments in LUAD cell lines, we found that USP42 is significantly overexpressed in LUAD, and its high expression is associates with advanced stages and reduced overall survival. Besides, USP42 knockdown suppressed proliferation, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanistically, USP42 physically interacted with PTGS2, thereby stabilizing PTGS2 from proteasomal degradation. Mouse Lewis lung carcinoma (LLC) cells with USP42 knockdown were subcutaneously injected into C57BL/6 mice. Our results demonstrated that USP42 depletion attenuated tumor growth, reduced PTGS2 and PD-L1 expression, alleviated CD8⁺ T cell exhaustion, and increased intratumoral CD8⁺ T cell infiltration. Importantly, forced PTGS2 expression largely rescued the tumor-suppressive phenotypes induced by USP42 knockdown, confirming PTGS2 as a critical downstream effector of USP2. In conclusion, our findings identify USP42 as a novel oncogenic deubiquitinase in LUAD that promotes tumor progression and immune escape by deubiquitinating and stabilizing PTGS2, and targeting USP42 is a promising strategy against LUAD.