Roles of JAMM-family deubiquitinase STAMBPL1 in cellular homeostasis and human cancer.

STAM-binding protein-like 1 (STAMBPL1, also termed AMSH-LP) is a conserved zinc-dependent metalloprotease deubiquitinase of the JAMM family, distinguished by its exquisite specificity for Lys63-linked polyubiquitin chains. Its unique bipartite structural recognition mode underpins this linkage selectivity, enabling it to orchestrate diverse physiological processes spanning endosomal trafficking, apoptosis regulation, metabolic homeostasis, immune signaling, and epithelial-mesenchymal plasticity. Aberrant STAMBPL1 upregulation is widely documented across multiple human malignancies, consistently correlating with advanced clinicopathological features and unfavorable patient survival. Mechanistically, it drives the malignant phenotype through both catalytic and noncatalytic mechanisms: it stabilizes multiple oncogenic substrates and thereby hyperactivates core pathways, including JAK2/STAT3, mTORC1, and NF-κB, to promote tumor proliferation, metastasis, chemotherapy resistance, and immune escape. Preclinical studies have validated the remarkable antitumor efficacy of STAMBPL1-targeting strategies ranging from natural-product modulators to peptide inhibitors and engineered ubiquitin variants. This review systematically integrates advances in STAMBPL1 biology from structural to translational studies, highlighting its promise as a therapeutic target for precision cancer therapy.