ATXN3 (ataxin 3) is a deubiquitinating enzyme that plays critical roles in protein homeostasis, transcriptional regulation, and cellular stress responses 1. As a deubiquitinase, ATXN3 specifically targets K48-K63-branched ubiquitin chains and facilitates lysosome regeneration after membrane damage by promoting degradation of LAMP2 through microautophagy 2. ATXN3 functions as a debranching enzyme for complex ubiquitin chains, working alongside VCP/p97-associated proteins 3. The protein exhibits tissue-specific tumor regulatory functions: in colon adenocarcinoma, ATXN3 acts as a tumor suppressor by stabilizing Galectin-9 through deubiquitination, thereby promoting cancer cell apoptosis 4. Conversely, ATXN3 promotes tumor immune evasion in other cancers by functioning as a positive regulator of PD-L1 transcription through deubiquitination of transcription factors including JunB 5. Clinically, CAG trinucleotide repeat expansion in the ATXN3 gene causes spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, which may be the most common dominantly inherited ataxia worldwide 6. This polyglutamine expansion leads to protein misfolding and accumulation, characteristic of polyglutamine neurodegenerative diseases 6.