Third Affiliated Hospital of Harbin Medical University

Aberrant lysine 2-hydroxyisobutyrylation (Khib) is a novel post-translational modification implicated in tumor progression, but its role in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Here, we identify a specific Khib modification at lysine 97 (K97) of the oncogenic transcription factor ETV4, which is significantly upregulated in ICC and strongly associated with tumor metastasis and poor patient outcomes. Functional assays demonstrate that ETV4 K97-Khib enhances ICC cell proliferation, invasion, and distant metastasis by promoting ferroptosis resistance. Mechanistically, ETV4 K97-Khib represses transcription of the ferroptosis inducer TXNIP and simultaneously facilitates its post-translational degradation through upregulation of the SUMO E3 ligase ZBED1, leading to increased SUMOylation of TXNIP. This dual mechanism reduces TXNIP levels and potently suppresses ferroptosis. KAT2A and HDAC1 were identified as the acyltransferase and deacylase controlling ETV4 Khib dynamics, respectively. Notably, the small-molecule compound thiostrepton significantly inhibits ETV4 K97-Khib, thereby promoting ferroptosis and suppressing ICC cell migration, invasion, and lung metastasis. Together, our study reveals a novel ETV4 Khib-driven mechanism underlying ferroptosis suppression and malignant progression in ICC, and highlights ETV4 Khib as a potential therapeutic target in cholangiocarcinoma.

Breast cancer is the most common malignancy in women and a major cause of cancer-related mortality. While early-stage disease is often curable, many patients ultimately develop distant metastases, with the brain representing one of the most devastating sites. Breast cancer brain metastasis (BCBM) is particularly prevalent in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes, leading to severe neurological symptoms, diminished quality of life, and poor prognosis. Despite progress in systemic therapy for primary tumors, outcomes for patients with BCBM remain poor, and these patients are frequently excluded from clinical trials. The pathogenesis of BCBM involves complex interactions between tumor cells and the central nervous system microenvironment. Crossing the blood-brain barrier and adapting to the brain niche requires tumor-stroma crosstalk, including signaling with astrocytes and microglia, which promotes immune evasion, therapeutic resistance, and metastatic outgrowth. Although advances in preclinical models and molecular profiling have provided valuable insights, critical mechanisms remain incompletely understood. Systemic therapies are increasingly important, with HER2-targeted agents, tyrosine kinase inhibitors, and subtype-specific regimens showing activity. Novel approaches, including poly (ADP-ribose) polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase inhibitors, and antibody-drug conjugates, are under evaluation. This review synthesizes epidemiology, molecular mechanisms, and emerging therapies of BCBM, underscoring advances achieved and highlighting the urgent need for novel targeted strategies and inclusive clinical trials.

Chimeric antigen receptor T (CAR-T) cell therapy faces critical barriers in solid tumors, including poor infiltration, T cell exhaustion, and immunosuppressive microenvironments, resulting in response rates below 10%. Herein, we engineered an inhalable nanoplatform using induced pluripotent stem cell-derived exosomes (IEXOs) displaying bispecific PD-1/mesothelin (MSLN) single-chain variable fragments (scFv) and loaded with indole-3-propionic acid (IPA) for metabolic reprogramming. IEXOs demonstrated high yield and intrinsic antitumor properties, inhibiting Lewis lung carcinoma (LLC) cell proliferation and migration. The bispecific exosomes loaded with IPA (BIEXO@IPA) achieved efficient pulmonary delivery via nebulization with 79.3% tumor cell-specific uptake versus 47.9% for liposomes in orthotopic lung cancer models. BIEXO@IPA treatment reduced tumor burden by 87.9% and achieved 80% survival at 80 days. Mechanistically, BIEXO@IPA bridged PD-1+ T cells to MSLN+ tumor cells through bispecific engagement while expanding progenitor exhausted T (Tpex) cells and reducing regulatory T cells. When combined with CAR-T cells, BIEXO@IPA achieved 66.7% complete remission with 100% survival at 80 days and 83.3% resistance to tumor rechallenge. Safety assessments revealed minimal toxicity. This BIEXO@IPA platform represents a scalable, clinically translatable strategy that addresses fundamental CAR-T limitations in solid tumors through synergistic multimodal immunomodulation.

BackgroundMyocardial fibrosis, characterized by excessive collagen deposition and fibroblast activation, is a pivotal pathological process driving heart failure after myocardial infarction (MI). Our prior research revealed that Brahma-related gene 1 (BRG1) expression is elevated after MI and exacerbated cardiac electrophysiological remodeling; however, its precise role and molecular mechanism in post-MI fibrosis remain undefined.MethodsBRG1 expression was assessed in a mouse MI model and in TGF-β1-stimulated cardiac fibroblasts (CFs). Gain- and loss-of-function studies were performed using adenoviral vectors, siRNA, and plasmids in vitro and in vivo. Cardiac function and fibrosis were evaluated by echocardiography and histology. The molecular mechanism was dissected through co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional rescue experiments targeting the PP2A/Smad3 axis.ResultsBRG1 was upregulated in fibrotic mouse hearts post-MI and in activated CFs. In vivo, BRG1 knockdown via AAV9-shRNA improved cardiac function, reduced infarct size, and attenuated fibrosis. In vitro, BRG1 promoted CFs proliferation, migration, and collagen production. Mechanistically, TGF-β1 enhanced the interaction between BRG1 and the transcription factor ZEB1. This complex transcriptionally repressed Ppp2r1a, the gene encoding the PP2A structural subunit Aα, leading to diminished PP2A activity. Consequently, Smad3 phosphorylation and nuclear translocation were enhanced, amplifying the pro-fibrotic TGF-β/Smad3 cascade. Crucially, ZEB1 knockdown or PP2A inhibition (okadaic acid) could respectively block or rescue the fibrotic effects of BRG1. Finally, BRG1 knockdown similarly suppressed fibrotic activation in human CFs.ConclusionOur study defines a novel BRG1/ZEB1/PP2A transcriptional axis as a key driver of myocardial fibrosis and suggests BRG1 as a potential therapeutic target for mitigating fibrotic remodeling after MI.