USP44 Stabilizes MAOB via Deubiquitination to Inhibit Cisplatin Resistance in Lung Adenocarcinoma

<h4>Background</h4>Cisplatin (DDP), as a commonly used chemotherapeutic agent for the clinical treatment of lung adenocarcinoma (LUAD), serves a key function in suppressing tumor progression; however, the development of tumor cell resistance has restricted its clinical application.<h4>Methods</h4>Differentially expressed genes (DEGs) between A549 and A549-DDP cells in the GEO dataset (GSE157692) were analyzed, and DDP resistance-related targets were downloaded from GeneCards; candidate genes were obtained via their intersection. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were conducted on candidate genes. Subsequently, key gene expression was analyzed via GEPIA and TCGA databases and verified by Western blot. Cell proliferation, apoptosis, migration, and invasion were detected by CCK-8, colony formation, flow cytometry, and Transwell assays. The interaction between MAOB and USP44 was predicted by UbiBrowser, and their regulatory relationship was validated using coimmunoprecipitation (Co-IP) and cycloheximide (CHX) chase assays.<h4>Results</h4>Monoamine oxidase B (MAOB) was identified as a core target. MAOB showed reduced expression in DDP-resistant LUAD cells and tumor tissues, with low levels linked to worse prognosis. MAOB overexpression enhanced DDP sensitivity, repressed cell proliferation/migration/invasion, promoted apoptosis, and reversed epithelial-mesenchymal transition (EMT). Ubiquitin-specific protease 44 (USP44) was downregulated in DDP-resistant LUAD models and stabilized MAOB via deubiquitination. MAOB knockdown reversed USP44 overexpression's effects on DDP resistance and malignant phenotypes.<h4>Conclusion</h4>USP44 promoted MAOB protein stability via deubiquitination, and the USP44-MAOB axis inhibited DDP resistance and malignant phenotypes of LUAD cells. This axis is thus a potential therapeutic target for improving DDP resistance in LUAD, providing a new direction for clinical intervention.