Hematopoietic progenitor kinase 1 (HPK1) has emerged as a compelling target for tumor immunotherapy due to its pivotal role in regulating key cellular processes, including survival, migration, apoptosis, and autophagy. In this comprehensive study, we characterized the pharmacological profile of a novel HPK1 inhibitor HDM2004 (compound 37). Through systematic structure-activity relationship (SAR) optimization, HDM2004 was identified as a highly potent HPK1 inhibitor (IC50 = 1.89 nM) with >30-fold selectivity over the closely related kinase GLK. The compound exhibits favorable drug-like properties, including high metabolic stability (human liver microsomal half-life >300 min) and minimal inhibition of cytochrome P450 enzymes (IC50 > 10 μM). Pharmacokinetic (PK) studies across multiple species demonstrated dose-proportional exposure, excellent oral bioavailability, and favorable tissue distribution. Importantly, HDM2004 displayed synergistic antitumor activity when combined with PD-L1 blockade in syngeneic mouse models, while maintaining an acceptable safety profile. Collectively, these data support HDM2004 as a promising preclinical candidate for combination cancer immunotherapy.

BackgroundGlioma heterogeneity and therapeutic resistance are closely linked to dysregulated programmed cell death (PCD). While individual PCD pathways have been studied, the integrated network of multi-modal PCD interactions and their clinical implications in glioma remain poorly understood. This study aims to decipher the interplay between 30 distinct PCD modalities and the immune microenvironment, developing a robust prognostic signature to guide therapy.MethodsThis study integrated 2,743 glioma samples from TCGA, CGGA, and GEO databases, encompassing RNA-seq, single-cell transcriptomic (GSE167960), and mutational data. Through literature mining and GeneCards database screening, 30 programmed cell death (PCD)-related gene sets (total 11,681 genes) were curated, identifying 428 differentially expressed genes (DEGs; |log2FC|>1, p < 0.05). A pan-death prognostic signature (Cell-Death Score, CDS) was constructed using 114 machine learning algorithm combinations, refined via CoxBoost to select 25 key genes. CIBERSORT quantified the abundance of 22 immune cell subsets, while ssGSEA assessed functional activity of 28 immune cell types. Drug sensitivity predictions employed GDSC database, with single-cell trajectory analysis validating molecular mechanisms and therapeutic strategies. In vitro, differential expression profiles of key genes were first examined between human normal astrocyte cell lines (SVG-P12) and three glioma cell lines (U87, U251, LN229). Subsequently, RNA-seq and qRT-PCR validated expression patterns of 25 key genes in tumor/adjacent non-tumorous tissues from 7 glioma patients. Finally, spatial transcriptomic data from 4 glioma tissue samples in our cohort (including two paired tumor-adjacent non-tumorous samples and two tumor-only samples) were integrated to delineate spatial expression patterns of key genes.ResultsIntegrated analysis of 2,743 public gliomas samples identified 428 cell death-associated differentially expressed genes, enriched in neuroactive ligand-receptor interactions and extracellular matrix regulation. Unsupervised clustering revealed distinct immune-activated and immune-silent patient subtypes. A pan-death prognostic signature (Cell-Death Score, CDS), constructed via multi-algorithm machine learning and optimized using CoxBoost to incorporate 25 key genes, demonstrated robust performance in training (1-/3-year AUC = 0.894/0.943) and validation cohort (C-index = 0.717), effectively stratifying high-risk patients (HR = 3.21, p < 0.0001). High-CDS patients displayed elevated tumor mutational burden, homologous recombination deficiency, and immune checkpoint expression, alongside enhanced sensitivity to 11 therapeutic agents, including gemcitabine. Single-cell trajectory analysis confirmed significant activation of model genes during glioma progression. A clinical nomogram integrating CDS, WHO grade and radiotherapy further improved prognostic utility. Based on in vitro cell line experiments, the expression profiles of 25 key genes demonstrated significant heterogeneity, with partial genes undetectable by qRT-PCR due to expression levels falling below detection thresholds. Among seven genes consistently detected across all 4 cell lines, tumor cell lines exhibited significantly upregulated expression relative to normal astrocyte counterparts. RNA-seq analysis revealed effective detection of 24/25 key genes in seven paired tumor/adjacent tissue samples, with 20 genes showing higher mean expression in tumor tissues. qRT-PCR validation confirmed upregulated trends for 12 detectable genes in tumor tissues. Spatial transcriptomic analysis further corroborated tumor region-specific overexpression of all 25 key genes compared to adjacent non-tumorous areas.ConclusionThe CDS signature unravels the molecular interplay between glioma cell death heterogeneity, immune dysregulation, and therapeutic resistance. This biomarker system provides both prognostic and therapeutic insights for precision oncology, paving the way for personalized combination therapies in glioma management.

IntroductionDiffuse high-grade gliomas are the most common malignant adult neuroepithelial tumors in humans and a leading cause of cancer-related death worldwide. The advancement of high throughput transcriptome sequencing technology enables rapid and comprehensive acquisition of transcriptome data from target cells or tissues. This technology aids researchers in understanding and identifying critical therapeutic targets for the prognosis and treatment of diffuse high-grade glioma.MethodsSpatial transcriptomics was conducted on two cases of isocitrate dehydrogenase (IDH) wild-type diffuse high-grade glioma (Glio-IDH-wt) and two cases of IDH-mutant diffuse high-grade glioma (Glio-IDH-mut). Gene set enrichment analysis and clustering analysis were employed to pinpoint differentially expressed genes (DEGs) involved in the progression of diffuse high-grade gliomas. The spatial distribution of DEGs in the spatially defined regions of human glioma tissues was overlaid in the t-distributed stochastic neighbor embedding (t-SNE) plots.ResultsWe identified a total of 10,693 DEGs, with 5,677 upregulated and 5,016 downregulated, in spatially defined regions of diffuse high-grade gliomas. Specifically, SPP1, IGFBP2, CALD1, and TMSB4X exhibited high expression in carcinoma regions of both Glio-IDH-wt and Glio-IDH-mut, and 3 upregulated DEGs (SMOC1, APOE, and HIPK2) and 4 upregulated DEGs (PPP1CB, UBA52, S100A6, and CTSB) were only identified in tumor regions of Glio-IDH-wt and Glio-IDH-mut, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses revealed that upregulated DEGs were closely related to PI3K/Akt signaling pathway, virus infection, and cytokine-cytokine receptor interaction. Importantly, the expression of these DEGs was validated using GEPIA databases. Furthermore, the study identified spatial expression patterns of key regulatory genes, including those involved in protein post-translational modification and RNA binding protein-encoding genes, with spatially defined regions of diffuse high-grade glioma.DiscussionSpatial transcriptome analysis is one of the breakthroughs in the field of medical biotechnology as this can map the analytes such as RNA information in their physical location in tissue sections. Our findings illuminate previously unexplored spatial expression profiles of key biomarkers in diffuse high-grade glioma, offering novel insight for the development of therapeutic strategies in glioma.

Glioblastoma (GBM) originates from glial cells, and complete surgical resection followed by radiotherapy and chemotherapy is the current standard treatment. However, gliomas are subjected to not only accelerated cell death after radiotherapy and chemotherapy but also cellular senescence. Senescent cells produce a senescence-associated secretory phenotype (SASP), which has a dual effect on the tumor microenvironment. The "one-two punch" strategy of specifically eliminating senescent cells and inhibiting SASP-derived secretions provides a new direction for tumor therapy. In this article, we review the mechanisms that mediate tumor cellular senescence and SASP, the elimination of senescent cells by senolytics for SASP inhibition, and the current situation of the "one-two punch" strategy for the treatment of glioma.

Despite the essential roles of Frizzled receptors (FZDs) in mediating Wnt signaling in embryonic development and tissue homeostasis, ligands targeting FZDs are rare. A few antibodies and peptide modulators have been developed that mainly bind to the family-conserved extracellular cysteine-rich domain of FZDs, while the canonical binding sites in the transmembrane domain (TMD) are far from sufficiently addressed. Based on the recent structures of FZDs, we explored small-molecule ligand discovery by targeting TMD. From the ChemDiv library with ∼1.6 million compounds, we identified compound F7H as an antagonist of FZD7 with an IC50 at 1.25 ± 0.38 μM. Focusing on this hit, the structural dissection study, together with computing studies such as molecular docking, molecular dynamics simulation, and free energy perturbation calculations, defined the binding pocket with key residue recognition. Our results revealed the structural basis of ligand recognition and demonstrated the feasibility of structure-guided ligand discovery for FZD7-TMD.

Abnormal expression of 6-phosphofructo-2-kinase/fruc-tose-2,6-biphosphatase 4 (PFKFB4) is closely related to the occurrence and development of tumors, and PFKFB4 has been shown to function as a protein kinase. How-ever, the molecular mechanisms through which PFKFB4 functions in glioblastoma (GBM) remain poorly under-stood. Accordingly, in this study, we assessed the roles of PFKFB4 in GBM. Compared to in adjacent tissues, PFKFB4 was highly expressed in GBM, and its expression level was negatively correlated with the overall survival time. In addition, knockdown of PFKFB4 inhibited the proliferation and invasion of GBM cells and promoted apoptosis. In a xenograft tumor model, tumor growth was inhibited by knockdown of PFKFB4 using short hair-pin RNA. Further studies demonstrated that PFKFB4 is involved in regulating the AKT signaling pathway. Thus, PFKFB4 acts as a protein kinase to regulate GBM pro-gression by activating the AKT/forkhead box O1 path-way, which may be a potential therapeutic target in GBM.

This research aims to develop a prognostic glioma marker based on m6A/m5C/m1A genes and investigate the potential role in the tumor immune microenvironment. Data for patients with glioma were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). The expression of genes related to m6A/m5C/m1A was compared for normal and glioma groups. Gene Ontology and Kyoto Encyclopedia of Genes and Gene enrichment analysis of differentially expressed genes were conducted. Consistent clustering analysis was performed to obtain glioma subtypes and complete the survival analysis and immune analysis. Based on TCGA, Lasso regression analysis was used to obtain a prognostic model, and the CGGA database was used to validate the model. The model-based risk scores and the hub genes with the immune microenvironment, clinical features, and antitumor drug susceptibility were investigated. The clinical glioma tissues were collected to verify the expression of hub genes via immunohistochemistry. Twenty genes were differentially expressed, Consensus cluster analysis identified two molecular clusters. Overall survival was significantly higher in cluster 2 than in cluster 1. Immunological analysis revealed statistically significant differences in 26 immune cells and 17 immune functions between the two clusters. Enrichment analysis detected multiple meaningful pathways. We constructed a prognostic model that consists of WTAP, TRMT6, DNMT1, and DNMT3B. The high-risk and low-risk groups affected the survival prognosis and immune infiltration, which were related to grade, gender, age, and survival status. The prognostic value of the model was validated using another independent cohort CGGA. Clinical correlation and immune analysis revealed that four hub genes were associated with tumor grade, immune cells, and antitumor drug sensitivity, and WTAP was significantly associated with microsatellite instability(MSI). Immunohistochemistry confirmed the high expression of WTAP, DNMT1, and DNMT3B in tumor tissue, but the low expression of TRMT6. This study established a strong prognostic marker based on m6A/m5C/m1A methylation regulators, which can accurately predict the prognosis of patients with gliomas. m6A/m5C/m1A modification mode plays an important role in the tumor microenvironment, can provide valuable information for anti-tumor immunotherapy, and have a profound impact on the clinical characteristics.

Target identification is an essential step in drug discovery. It facilitates an understanding of drug action and potential toxicities and offers opportunities to repurpose drug candidates. HP-1, a potent EGFRL858R/T790M (epidermal growth factor receptor) mutant inhibitor, was developed by the group in an effort to treat acquired resistance in nonsmall cell lung cancer (NSCLC), but its cellular off-targets were not identified. An activity-based probe, HJ-1, was created followed by chemical proteomics and bioimaging studies. A total of 13 protein hits, including EGFR and NT5DC1, were identified by pull-down/LC-MS. Subsequent validation experiments indicated the involvement of a major off-target, NT5DC1, in the biological function of HP-1.

The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.

目的 探讨异物经颈静脉孔致非火器性颅脑穿通伤(PBI)的诊断与治疗方式.方法 回顾分析1例异物颈静脉孔刺入左侧小脑患儿的临床资料;并对相关文献进行复习.结果 患儿女,3岁,进食时摔倒致筷子插入咽部,家人自行拔除大部分异物(不完整),伤后患儿出现咽痛、头痛、恶心、呕吐.颅脑CT、MRI、CTA检查示,左侧小脑局限水肿,筷子经口腔-去侧咽侧壁-颅底-颈静脉孔-去侧小脑.于全麻条件下经左侧乙状窦后入路开颅将异物完全取出.术后患者恢复良好,无发生颅内出血、感染等并发症及后遗症.结论 对于经颈静脉孔致非火器类颅脑贯通伤患者,早期完善影像学检查,严谨手术操作,积极防治并发症,可显著改善患者的预后.

Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.

冠蛋白(Coronins)是一个高度进化的保守蛋白家族.Coronin 3(Coronin 1c,CRN2)是其家族中的一员,其在肌动蛋白网络的重组中起重要作用,并与突起形成、分泌、迁移和侵袭等细胞过程有关.多项研究表明其在胶质瘤、前列腺癌、胃癌、黑色素瘤、肺癌、肝癌、三阴乳腺癌、食管癌等多种恶性肿瘤中表达上升.有研究显示Coronin 3蛋白对恶性肿瘤有促进转移和侵袭的作用.本文就目前研究Coronin 3对不同恶性肿瘤的作用及其作用机制的进展进行综述.

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low μM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.

Background: Fructose-2,6-biphosphatase 4 (PFKFB4) is a key enzyme in glucose metabolism, and its differential expression is closely related to the occurrence and development of tumors. However, the related molecular mechanisms in glioblastoma(GBM) remain unclear. Methods: Firstly, the expression of PFKFB4 in normal and GBM tissues was analyzed by bioinformatics in The Cancer Genome Atlas (TCGA) database, and the relationship between PFKFB4 and survival was analyzed. Then detected the expression of PFKFB4 in tissues and cells of glioma. After PFKFB4 Interference, observed the proliferation by CCK8 and EDU, apoptosis of U87 cells by flow cytometry. the content of ATP and mitochondrial membrane function were detected. The possible interaction mechanism between PFKFB4 and mitochondria was analyzed by bioinformatics and verified by qPCR and Western blotting(WB). Finally, the experiment of subcutaneous tumor formation in nude mice was verified. Results: Our study found that PFKFB4 is highly expressed in glioma tissues and cell lines. High expression levels are associated with a poor prognosis. In addition, PFKFB4 inhibition attenuates the proliferation and mitochondrial function of cancer cells promotes apoptosis, and can also reduce ATP levels. Further studies showed that PFKFB4 affects the metabolic reprogramming of gliomas by regulating mitochondrial membrane fusion, Regulating the protein expression of mitofusin 1(MFN1), mitofusin 2(MFN2), opticatrophy-1(OPA1). Animal studies verify these results. Conclusion: PFKFB4 may be a potential therapeutic target for glioma.

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3'-(imidazo[1,2-a]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC50 = 1740 nM) and negligible activities against Bcr-Abl (IC50 > 10 μM) and c-Kit (IC50 > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

Protein modification by chemical reagents has played an essential role in the treatment of human diseases. However, the reagents currently used are limited to the covalent modification of cysteine and lysine residues. It is thus desirable to develop novel methods that can covalently modify other residues. Despite the fact that the carboxyl residues are crucial for maintaining the protein function, few selective labeling reactions are currently available. Here, we describe a novel reactive probe, 3-phenyl-2H-azirine, that enables chemoselective modification of carboxyl groups in proteins under both in vitro and in situ conditions with excellent efficiency. Furthermore, proteome-wide profiling of reactive carboxyl residues was performed with a quantitative chemoproteomic platform.

Abstract Background: Glioma is the most common type of brain tumor because of the destructiveness of the disease itself and the side effects of treatment, patients often leave symptoms of neurological defects. At present, rehabilitation treatment is not popular in glioma patients. There is a lack of definite evidence to prove the benefits of rehabilitation therapy for glioma patients. The purpose of this meta-analysis is to determine whether rehabilitation therapy can significantly improve the prognosis of neurological function and improve the quality of life of patients with glioma. Methods: The articles about rehabilitation treatment of glioma in Cochrane, PubMed, and Embase, Web of Science, and Medline database from January 1990 to May 2020 were searched. Before rehabilitation as the control group, after rehabilitation as the experimental group. The Functional Independence Measure (FIM) was used as the outcome index, including total FIM, motor FIM, and cognitive FIM. Use STATA12.0 for meta-analysis. Results: A total of 8 articles were included in the study, with a total of 375 glioma patients. Meta-analysis of total FIM (SMD = 0.96, 95%CI = 0.66–1.26, P < .001), motor FIM (SMD = 0.75, 95%CI = 0.54–0.96, P < .001) and cognitive FIM (SMD = 0.35, 95%CI = 0.19–0.50, P < .001) indicated that the neurological function of rehabilitation was significantly improved in total, motor and consciousness. Conclusion: The published studies show that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. More attention should be paid to the therapeutic value of rehabilitation for glioma patients in the future. PROSPERO registration number: PROSPERO CRD42020188740.

Background: Glioma is the most common type of brain tumor because of the destructiveness of the disease itself and the side effects of treatment, patients often leave symptoms of neurological defects. At present, rehabilitation treatment is not popular in glioma patients. There is a lack of definite evidence to prove the benefits of rehabilitation therapy for glioma patients. The purpose of this meta-analysis is to determine whether rehabilitation therapy can significantly improve the prognosis of neurological function and improve the quality of life of patients with glioma. Methods: The articles about rehabilitation treatment of glioma in Cochrane, PubMed, and Embase, Web of Science, and Medline database from January 1990 to May 2020 were searched. Before rehabilitation as the control group, after rehabilitation as the experimental group. The Functional Independence Measure (FIM) was used as the outcome index, including total FIM, motor FIM, and cognitive FIM. Use STATA12.0 for meta-analysis. Results: A total of 8 articles were included in the study, with a total of 375 glioma patients. Meta-analysis of total FIM (SMD = 0.96, 95%CI = 0.66-1.26, P < .001), motor FIM (SMD = 0.75, 95%CI = 0.54-0.96, P < .001) and cognitive FIM (SMD = 0.35, 95%CI = 0.19-0.50, P < .001) indicated that the neurological function of rehabilitation was significantly improved in total, motor and consciousness. Conclusion: The published studies show that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. More attention should be paid to the therapeutic value of rehabilitation for glioma patients in the future. PROSPERO registration number: PROSPERO CRD42020188740.

Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor “retinoic acid receptor-related orphan receptor gamma-t” (RORγt), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of RORγt and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting RORγt. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (both P = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-γ(Th1) and TGF-β(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood–retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that RORγt inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.