Yingli Wu

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.

Objective Dysregulation of M1/M2 macrophage polarization drives sepsis and impaired wound healing. Deubiquitinases (DUBs) are promisingdrug targets, but the role of ubiquitin-specific protease 47 (USP47) in macrophage plasticity remains unclear. This study investigated the regulatoryfunction of USP47 in macrophage polarization and its therapeutic potential for inflammatory disorders. Methods In vitro, human THP-1 and mouse bonemarrow-derived macrophages were polarized, with USP47 modulated via genetic manipulation or the inhibitor P22077. In vivo, LPS-induced septicperitonitis and cutaneous wound models were used to evaluate the effects of Usp47 deficiency or P22077 treatment. Mechanistically, protein interactionand ubiquitination assays were performed to verify the USP47-YAP axis and downstream signaling. Results USP47 was upregulated in M1 macrophagesand downregulated in M2 macrophages. USP47 inhibition skewed macrophages toward the M2 phenotype. In vivo , Usp47 knockout or P22077 treatmentimproved survival in septic mice, reduced systemic inflammation, and accelerated wound healing, accompanied by increased M2 infiltration at lesion sites.Mechanistically, USP47 directly deubiquitinated and stabilized YAP protein; stabilized YAP drove M1 polarization via two parallel axes: nucleartranslocation to promote pro-inflammatory cytokine transcription, and promotion of NLRP3 inflammasome stabilization. Conclusions USP47 is a critical regulator of macrophage polarization via the USP47-YAP-NLRP3 axis. Targeting USP47 exerts anti-inflammatory and pro-repair effects, representing a promising therapeutic strategy for sepsis and wound healing disorders.

ATXN3 has recently emerged as a pro-oncogenic deubiquitinating enzyme (DUB) involved in the progression of multiple cancers, including breast and prostate cancer. However, the therapeutic potential of targeting ATXN3 remains largely unexplored due to the lack of effective inhibitors. In this study, we performed an Ub-AMC-based high-throughput screening assay using full-length ATXN3 and identified YL064, a derivative of the natural product sinomenine isolated from Sinomenium acutum , as a novel ATXN3 inhibitor. Direct interaction between YL064 and ATXN3 was confirmed by thermal shift assay, cellular thermal shift assay, surface plasmon resonance, and molecular docking analysis. Functionally, YL064 suppressed cancer cell proliferation, induced cell-cycle arrest, and reduced metastatic potential. Mechanistically, YL064 inhibited ATXN3 deubiquitinating activity and promoted the ubiquitination and proteasomal degradation of ATXN3 substrates, including KLF4 and YAP. Furthermore, YL064 significantly inhibited tumor growth in an orthotopic breast cancer model in vivo. Collectively, our findings establish YL064 as a promising ATXN3 inhibitor that targets the ubiquitin-proteasome pathway to exert anti-tumor effects, highlighting its potential as a novel therapeutic agent for ATXN3-driven cancers.

Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a critical challenge in lung adenocarcinoma. Here, we identify ATXN3, a deubiquitinating enzyme, as a driver of Osimertinib resistance and a predictor of poor patient survival. Osimertinib treatment dynamically upregulates ATXN3 transcription, which stabilizes USP25 through deubiquitination, activating an ATXN3-USP25-TRMT1 signaling cascade. This axis enhances TRMT1-mediated tRNA m² ₂ G modifications, enabling selective translation of redox-regulating enzymes (e.g., GPX4, SOD2) that scavenge reactive oxygen species (ROS) and mitigate drug-induced oxidative stress. Genetic ablation of TRMT1 or pharmacological targeting of USP25 with the small-molecule inhibitor AZ1 disrupted this pathway, restored ROS accumulation, and re-sensitized resistant tumors to Osimertinib in patient-derived organoids and in vivo models. Our findings reveal tRNA epitranscriptomic reprogramming as a novel mechanism of EGFR-TKI resistance and position the ATXN3/USP25/TRMT1 axis as a therapeutically actionable target to overcome Osimertinib resistance in lung cancer.

Eradicating leukemic stem cells (LSCs), a major driver of primary resistance and relapse in chronic myeloid leukemia (CML) following tyrosine kinase inhibitor (TKI) treatment, is critical for achieving a cure. Previously, we identified that ANP32B promotes CML LSCs' survival and leukemogenesis by directly binding and inhibiting p53 activity, suggesting a therapeutic opportunity. Here, we show that 1-amino-8-naphthol-2,4-disulfonic acid (ANDS) binds unacetylated p53 and restores p53 activity by disrupting ANP32B-p53 interaction. Consequently, ANDS inhibits CML cell proliferation, impairs LSC function and prolongs survival in the CML mouse model while sparing normal progenitor cells. Based on notion that ANDS, as a previously-identified CaMKP inhibitor, potentially activates p-CaMKIIγ to accelerate CML progression, we find that ANDS combination with KN93, a p-CaMKIIγ inhibitor, synergistically suppresses both TKI-sensitive and -resistant CML. Thus, we highlight that ANDS alone or in combination with CaMKP inhibitor could become a therapeutic strategy for eradicating LSCs and overcoming TKI-resistance in CML.

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations, found in 25%–30% of Acute myeloid leukemia (AML) patients, cause poor prognosis and resistance to FLT3 tyrosine kinase inhibitors (TKIs). We show that APG-115 selectively kills FLT3-ITD cells by activating p53. This critically upregulates TRIM22 (Tripartite motif-containing protein 22), an essential E3 ubiquitin ligase that directly binds FLT3-ITD, promotes its polyubiquitination, and induces its proteasomal degradation. This TRIM22-mediated mechanism offers a novel strategy to overcome intrinsic and acquired TKI resistance. Unlike inhibitors such as AC220, which suppress FLT3 signaling but downregulate p53, APG-115 restores p53 function and induces TRIM22, enabling potent synergy with FLT3 inhibitors. TRIM22 is essential for APG-115’s suppression of leukemia stem cells (LSCs), inducing cell cycle arrest, myeloid differentiation, and reduced clonogenic potential. The combination of APG-115 and AC220 significantly enhances apoptosis in FLT3-ITD AML models and primary cells, while sparing normal cells. It shows robust efficacy in preclinical xenograft models, reducing tumor burden and extending survival. This work establishes targeting the p53/TRIM22 axis, reliant on TRIM22’s unique activity against FLT3-ITD, as a highly promising therapeutic approach for FLT3-ITD AML, including resistant disease.

Acute myeloid leukemia (AML) remains a challenging hematologic malignancy with limited treatment options and poor prognosis. Here, we report the development of a multifunctional, pH-responsive, and biodegradable nanoparticle system, Membrane/Cu-HMPB@DSF/RSL3, for synergistic AML therapy. Constructed upon the Prussian blue-based frameworks and cloaked with leukemia cell membranes, these nanoparticles preferentially accumulate in AML cells and release copper, iron, and manganese ions, along with disulfiram (DSF) and RSL3, under mildly acidic intracellular conditions. The released metal ions catalyze Fenton-like reactions, deplete intracellular glutathione (GSH), and induce ferroptosis and cuproptosis in cooperation with the loaded small-molecule drugs. Meanwhile, manganese ions activate the cGAS-STING pathway, triggering innate immune responses and promoting immune cell recruitment. Both in vitro and in vivo studies demonstrated robust anti-AML efficacy with minimal systemic toxicity. This work presents a modular and immunogenic nanoplatform that holds broad potential for AML treatment and beyond. Graphical abstract

Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a critical challenge in lung adenocarcinoma. Here, we identify ATXN3, a deubiquitinating enzyme, as a driver of Osimertinib resistance and a predictor of poor patient survival. Osimertinib treatment dynamically upregulates ATXN3 transcription, which stabilizes USP25 through deubiquitination, activating an ATXN3-USP25-TRMT1 signaling cascade. This axis enhances TRMT1-mediated tRNA m²2G modifications, enabling selective translation of redox-regulating enzymes (e.g., GPX4, SOD2) that scavenge reactive oxygen species (ROS) and mitigate drug-induced oxidative stress. Genetic ablation of TRMT1 or pharmacological targeting of USP25 with the small-molecule inhibitor AZ1 disrupted this pathway, restored ROS accumulation, and re-sensitized resistant tumors to Osimertinib in patient-derived organoids and in vivo models. Our findings reveal tRNA epitranscriptomic reprogramming as a novel mechanism of EGFR-TKI resistance and position the ATXN3/USP25/TRMT1 axis as a therapeutically actionable target to overcome Osimertinib resistance in lung cancer.