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Last update 23 Jan 2025

GZMK

Last update 23 Jan 2025

Basic Info

Synonyms

Fragmentin-3, Granzyme K, granzyme K (granzyme 3; tryptase II)

+ [8]

Introduction-

Drugs associated with GZMK

VDA-007

Target

GZMK

Mechanism

GZMK modulators

Active Org.

viDA Therapeutics, Inc.

Originator Org.

viDA Therapeutics, Inc.

Active Indication

Immune System Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VDA-002

Target

GZMK

Mechanism

GZMK modulators

Active Org.

viDA Therapeutics, Inc.

Originator Org.

viDA Therapeutics, Inc.

Active Indication

Immune System Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GZMK

100 Translational Medicine associated with GZMK

0 Patents (Medical) associated with GZMK

378

Literatures (Medical) associated with GZMK

01 Feb 2025·eBioMedicine

Clonal GZMK+CD8+ T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation

Article

Author: Shi, Jiawei ; Yin, Weiwei ; Gao, Yang ; Chen, Zhi ; Xiao, Haowen ; Pan, Wenjue ; Zeng, Xun ; Luo, Yi ; Yue, Xiaoyan ; Liu, Ruixiang ; Shan, Wei ; Zhao, Xiujie ; Zhou, Hongyu ; Zhang, Jie

BACKGROUNDBronchiolitis obliterans syndrome (BOS) is one of the most devastating outcomes of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This remains an area of unmet clinical need for optimal therapy for BOS patients partly due to the limited understanding of pathogenic mechanisms.METHODSWe collected blood samples from 22 patients with cGVHD and 11 patients without cGVHD following allo-HSCT. By applying a combination of mass cytometry (CyTOF), RNA-sequencing and the quantitative cytokine array, we discovered a new cellular hallmarker of patients with cGVHD-BOS. This finding was further validated in cGVHD-BOS murine models by using single-cell RNA sequencing (scRNA-seq) and paired single-cell V(D)J sequencing analyses.FINDINGSWe revealed that circulating Granzyme K (GZMK)-expressing CD8⁺ T cells with increased expression of CCR5 were accumulated in cGVHD-BOS patients, and GZMK can induce the expression of fibrosis-essential proteins, collagen type I alpha 1 chain (COL1A1) and fibronectin (FN1), in human fibroblasts. As compared to those of control mice, GZMK⁺CD8⁺ T cells in the lungs of cGVHD-BOS mice were undergoing significant infiltration and clonal hyperexpansion, with more cytotoxic, pro-inflammatory, migratory and exhausted phenotypes. Moreover, we screened small-molecule drugs and revealed that Bosutinib, the second-generation BCR-ABL1-targeting tyrosine kinase inhibitor (TKI), could inhibit GZMK expression in CD8⁺ T cells and reduce lung stiffness and pulmonary fibrosis in cGVHD-BOS mice.INTERPRETATIONThis study provides proof-of-principle evidence for clonal GZMK⁺CD8⁺ T cells as an unexplored contributor to the pathogenesis of cGVHD-BOS, which can be an underlying biomarker for treatment.FUNDINGThis work was supported by the National Natural Science Foundation of China (No. 82170141, 82100123, 81870136), and "Pioneer" and "Leading Goose" R&D Program of Zhejiang (grant No. 2022C03012).

31 Jan 2025·British Journal of Cancer

Integrated proteomics and scRNA-seq analyses of ovarian cancer reveal molecular subtype-associated cell landscapes and immunotherapy targets

Article

Author: Zhu, Fang ; Wang, Meng ; Qin, Jun ; Yang, Wenqing ; He, Qiongqiong ; Zhang, Yu ; Wang, Yi ; Xie, Bin ; Yang, Siyu ; Chen, Xiaodan ; Yuan, Kai ; Zheng, Nairen ; Sun, Lunquan ; Liu, Mingwei ; Tan, Rong ; Wen, Ming ; Zhan, Dongdong

AbstractBackgroundEpithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, yet understanding the connections between its molecular subtypes and their therapeutic implications remains incomplete.MethodsWe conducted mass spectrometry-based proteomics analyses of 154 EOC tumour samples and 29 normal fallopian tubes, and single-cell RNA sequencing (scRNA-seq) analyses of an additional eight EOC tumours to classify proteomic subtypes and assess their cellular ecosystems and clinical significance. The efficacy of identified therapeutic targets was evaluated in patient-derived xenograft (PDX) and orthotopic mouse models.ResultsWe identified four proteomic subtypes with distinct clinical relevance: malignant proliferative (C1), immune infiltrating (C2), Fallopian-like (C3) and differentiated (C4) subtypes. C2 subtype was characterized by lymphocyte infiltration, notably an increased presence of GZMK CD8+ T cells and phagocytosis-like MRC+ macrophages. Additionally, we identified CD40 as a specific prognostic factor for C2 subtype. The interaction between CD40+ phagocytosis-like macrophages and CD40RL+ IL17R CD4+ T cells was correlated with a favourable prognosis. Finally, we established a druggable landscape for non-immune EOC patients and verified a TYMP inhibitor as a promising therapeutic strategy.ConclusionsOur study refines the current immune subtype for EOC, highlighting CD40 agonists as promising therapies for C2 subtype patients and targeting TYMP for non-immune patients.

08 Jan 2025·Endocrine, Metabolic & Immune Disorders - Drug Targets

Identification of Biomarkers Related to Liquid-Liquid Phase Separation for Ulcerative Colitis Based on Single-Cell and Bulk RNA Transcriptome Sequencing Data

Article

Author: Chen, Bin ; Lu, Jicheng ; Lu, Xu

Background:Liquid-Liquid Phase Separation (LLPS) is a process involved in the formation of established organelles and various condensates that lack membranes; however, the relationship between LLPS and Ulcerative Colitis (UC) remains unclear.Aims:This study aimed to comprehensively clarify the correlation between ulcerative colitis (UC) and liquid-liquid phase separation (LLPS).Objectives:In this study, bioinformatics analyses and public databases were applied to screen and validate key genes associated with LLPS in UC. Furthermore, the roles of these key genes in UC were comprehensively analyzed.Methods:Based on the single-cell transcriptomic data of UC obtained from the Gene Expression Omnibus (GEO) database, differences between patients with UC and their controls were compared using the limma package. The single-cell data were then filtered and normalized by the ‘Seurat’ package and subjected to dimension reduction by the Uniform Manifold Approximation and Projection (UMAP) algorithm. The LLPS-related genes (LLPSRGs) were searched on the Dr- LLPS website to obtain cross-correlated genes, which were scored using the ssGSEA algorithm. Next, functional enrichment, interaction network, immune landscape, and diagnostic and drug prediction of the LLPSRGs were comprehensively explored. Finally, the results were validated using external datasets and quantitative real-time PCR (qRT-PCR).Results:A total of eight cell types in UC were classified, namely, fibroblasts, macrophages, endothelial cells, neutrophils, NK cells, B cells, epithelial cells, and T cells. The intersection between differently expressed genes (DEGs) among the eight cell types identified 44 key genes, which were predominantly enriched in immune- and infection-related pathways. According to receiver operating characteristic (ROC) curves, PLA2G2A, GZMK, CD69, HSP90B1, and S100A11 reached an AUC value of 0.94, 0.95, 0.86, 0.89, and 0.93, respectively. Drug prediction revealed that decitabine, tetrachlorodibenzodioxin, tetradecanoylphorbol acetate, thapsigargin, and cisplatin were the potential small molecular compounds for PLA2G2A, GZMK, CD69, HSP90B1, and S100A11. Immune cell infiltration analysis demonstrated that the infiltration of CD4 memory T cell activation, macrophage M1, T macrophage M0, neutrophils, and mast cell activation was higher in the UC group than in the normal groupConclusion:The LLPSRGs play crucial roles in UC and can be used as prognostic and diagnostic markers for UC. The current findings contribute to the management of UC.

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