MINDY1 (MINDY lysine 48 deubiquitinase 1) is a K48-linked polyubiquitin-specific deubiquitinase that regulates protein stability and cellular signaling pathways. The enzyme demonstrates exquisite specificity for cleaving K48-linked polyubiquitin chains through a non-canonical catalytic triad composed of Cys-His-Thr, with activity regulated by a Cys-loop autoinhibition mechanism that is relieved upon substrate binding 1. MINDY1 contains five distinct ubiquitin binding sites that enable it to sense both chain length and linkage type, with preference for longer polyubiquitin chains 1. The protein plays critical roles in multiple physiological processes, including embryonic stem cell self-renewal through polyamine-dependent regulation and prenylation-dependent mechanisms 2. In metabolic regulation, MINDY1 S441 serves as an AKT substrate involved in insulin signaling, where knockdown enhances insulin-stimulated glucose uptake 3. Clinically, MINDY1 has significant implications in cancer biology, where it stabilizes estrogen receptor α (ERα) in breast cancer cells through deubiquitination, promoting tumor proliferation 4, and facilitates immune escape in hepatocellular carcinoma by deubiquitinating PD-L1 via Wnt/β-catenin pathway activation 5. Additionally, genetic variants in MINDY1 are associated with exceptional responses to CDK4/6 inhibitor therapy in ER-positive breast cancer 6.