Negative regulator IL-1 receptor 2 (IL-1R2) and its roles in immune regulation of autoimmune diseases.

The decoy receptor interleukin 1 receptor 2 (IL-1R2), also known as CD121b, has different forms: membrane-bound (mIL-1R2), soluble secreted (ssIL-1R2), shedded (shIL-1R2), intracellular domain (IL-1R2ICD). The different forms of IL-1R2 exert not exactly similar functions. IL-1R2 can not only participate in the regulation of inflammatory response by competing with IL-1R1 to bind IL-1 and IL-1RAP, but also regulate IL-1 maturation and cell activation, promote cell survival, participate in IL-1-dependent internalization, and even have biological activity as a transcriptional cofactor. In this review, we provide a detailed description of the biological characteristics of IL-1R2 and discuss the expression and unique role of IL-1R2 in different immune cells. Importantly, we summarize the role of IL-1R2 in immune regulation from different autoimmune diseases, hoping to provide a new direction for in-depth studies of pathogenesis and therapeutic targets in autoimmune diseases.

Cobalt-Catalyzed Borylative Reduction of Azobenzenes to Hydrazobenzenes via a Diborylated-Hydrazine Intermediate.

Cobalt-catalyzed borylative reduction of azobenzenes using pinacolborane is developed. The simple cobalt chloride catalyst and reaction conditions make this protocol attractive for hydrazobenzene synthesis. This borylative reduction shows good functional group compatibility and can be readily scaled up to the gram scale. Preliminary mechanistic studies clarified the proton source of the hydrazine products. This cobalt-catalyzed azobenzene borylative reaction provides a practical protocol to prepare synthetically useful diborylated hydrazines.

DFT Calculations Rationalize Unconventional Regioselectivity in PdII-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes with Hydrazones.

Density functional theory (DFT) calculations have been conducted to gain insight into the unique formation of the branched alkylation product in the PdII-catalyzed defluorinative alkylation of gem-difluorocyclopropanes with hydrazones. The reaction is established to occur in sequence through oxidative addition, ß-F elimination, η1-η3 isomerization, transmetalation, η3-η1 isomerization, 3,3'-reductive elimination, deprotonation/N2 extrusion, and proton abstraction. The rate-determining step of the reaction is identified as the ß-F elimination, featuring an energy barrier of 28.6 kcal/mol. The 3,3'-reductive elimination transition states are the regioselectivity-determining transition states. The favorable noncovalent π-π interaction between the naphthyl group of gem-difluorocyclopropane and the phenyl group of hydrazone is found to be mainly responsible for the observed regioselectivity.

DFT Insight into a Strain-Release Mechanism in Bicyclo[1.1.0]butanes via Concerted Activation of Central and Lateral C-C Bonds with Rh(III) Catalysis.

Transition-metal-catalyzed, strain-release-driven transformations of "spring-loaded" bicyclo[1.1.0]butanes (BCBs) are considered potent tools in synthetic organic chemistry. Previously proposed strain-release mechanisms involve either the insertion of the central C-C bond of BCBs into a metal-carbon bond, followed by ß-C elimination, or the oxidative addition of the central or lateral C-C bond on the transition metal center, followed by reductive elimination. This study, employing DFT calculations on a Rh(III)-catalyzed model system in a three-component protocol involving oxime ether, BCB ester, and ethyl glyoxylate for constructing diastereoselective quaternary carbon centers, introduces an unusual strain-release mechanism for BCBs. In this mechanism, the catalytic reaction is initiated by the simultaneous cleavage of two C-C bonds (the central and lateral C-C bonds), resulting in the formation of a Rh-carbene intermediate. The new mechanism exhibits a barrier of 21.0 kcal/mol, making it energetically more favorable by 11.1 kcal/mol compared to the previously suggested most favorable pathway. This unusual reaction mode rationalizes experimental observation of the construction of quaternary carbon centers, including the excellent E-selectivity and diastereoselectivity. The newly proposed strain-release mechanism holds promise in advancing our understanding of transition-metal-catalyzed C-C bond activation mechanisms and facilitating the synthesis of transition metal carbene complexes.

PANoptosis Features, a Humanized NSG Murine Model of Sjogren's Syndrome.

Sjogren's syndrome (SS) is a complex systemic autoimmune disease. This study aims to elucidate a humanized NOD-PrkdcscidIl2rgem1/Smoc (NSG) murine model to better clarify the pathogenesis of SS. NSG female mice were adoptively transferred with 10 million peripheral blood mononuclear cells (PBMCs) through the tail vein from healthy controls (HCs), primary Sjogren's syndrome (pSS), and systemic lupus erythematosus (SLE) patients on D0. The mice were subcutaneously injected with C57/B6j submandibular gland (SG) protein or phosphate-buffered saline on D3, D17 and D31, respectively. NSG mice were successfully transplanted with human PBMCs. Compared with NSG-HC group, NSG-pSS and NSG-SLE mice exhibited a large number of lymphocytes infiltration in the SG, decreased salivary flow rate, lung involvement, decreased expression of genes related to salivary secretion, and the production of autoantibodies. Type I interferon-related genes were increased in the SG of NSG-pSS and NSG-SLE mice. The ratio of BAX/BCL2, BAX, cleaved caspase3, and TUNEL staining were increased in the SG of NSG-pSS and NSG-SLE mice. The expressions of p-MLKL and p-RIPK3 were increased in the SG of NSG-pSS and NSG-SLE mice. Increased expression of type I interferon-related genes, PANoptosis (apoptosis and necroptosis) were identified in the SG of this typical humanized NSG murine model of SS.

Immune landscape and progress in immunotherapy for pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (pitNETs) are the second most common primary brain tumors. Despite their prevalence, the tumor immune microenvironment (TIME) and its clinical implications remain largely unexplored. This review provides a comprehensive overview of current knowledge on the immune landscape and advancements in targeted immunotherapy for pitNETs. Macrophages and T cells are principal immune infiltrates within the TIME. Different subtypes of pitNETs display distinct immune patterns, influencing tumor progressive behaviors. PD-L1, the most extensively studied immune checkpoint, is prominently expressed in hormonal pitNETs and correlates with tumor growth and invasion. Cytokines and chemokines including interleukins, CCLs, and CXCLs have complex correlations with tumor subtypes and immune cell infiltration. Crosstalk between macrophages and pitNET cells highlights bidirectional regulatory roles, suggesting potential macrophage-targeted strategies. Recent preclinical studies have demonstrated the efficacy of anti-PD-L1 therapy in a mouse model of corticotroph pitNET. Moreover, anti-PD-1 and/or anti-CTLA-4 immunotherapy has been applied globally in 28 cases of refractory pitNETs, showing more favorable responses in pituitary carcinomas than aggressive pitNETs. In conclusion, the TIME of pitNETs represents a promising avenue for targeted immunotherapy and warrants further investigation.

Identification of EPSTI1 as a new potential biomarker for SLE based on GEO database.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with highly heterogeneous. The aim of this study is to find the key genes in peripheral blood mononuclear cells (PBMCs) of SLE patients and to provide a new direction for the diagnosis and treatment of lupus. METHODS: GSE121239, GSE50772, GSE81622, and GSE144390 mRNA expression profiles were obtained from the website of Gene Expression Omnibus (GEO), and differential expressed genes (DEGs) analysis was performed by R. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate signaling pathways for the DEGs. Real-time qPCR (RT-qPCR) was used to verify the key gene EPSTI1 in PBMCs of SLE patients. Finally, the correlation analysis and ROC curve analysis of EPSTI1 for SLE were performed. RESULTS: A total of 12 upregulated DEGs were identified, including MMP8, MX1, IFI44, EPSTI1, OAS1, OAS3, HERC5, IFIT1, RSAD2, USP18, IFI44L, and IFI27. GO and KEGG pathway enrichment analysis showed that those DEGs were mainly concentrated in the response to virus and IFN signaling pathways. Real-time qPCR (RT-qPCR) revealed that EPSTI1 was increased in PBMCs of SLE. EPSTI1 was positively correlated with SLEDAI score in SLE patients. Besides, EPSTI1 was positively correlated with T cell activation- or differentiation-associated genes (BCL6 and RORC). Furthermore, ROC analyses proved EPSTI1 may have diagnostic value for SLE. CONCLUSION: Together, EPSTI1 was found to be a potential biomarker for SLE, closely related to T cell immune imbalance. Key Points • EPSTI1 expression was significantly increased in PBMCs of SLE patients. • EPSTI1 was positively correlated with disease activity and T cell activation- or differentiation-associated genes in SLE patients. • EPSTI1 might have a good diagnostic value for SLE.

Proteome-metabolome profiling of wax gland complex reveals functional changes in honeybee, Apis mellifera L.

Wax gland complex (WGC) serves as the primary generator of beeswax; however, the dynamic biological function in wax secretion remains unclear. To elucidate the developmental mechanism of WGC, we conducted a comprehensive analysis to reveal the variations in proteins and metabolites among the newly emerged bee (NEB), wax-secreting bee (WSB), and overaged bee (OAB). We identified 3,295 proteins and 159 metabolites in WGC. Specifically, NEB elevated the expression of ribosomal proteins for preparing the glandular organ. While WSB promoted the size of epidermal cells and oenocytes, the enrichment of fatty acids and energy metabolism in WSB suggested a strong ability in wax synthesis. In OAB, disorganized wax tubules, and up-regulated cysteine proteases reflected the gland degeneration. These findings highlight the dynamic changes in the level of molecule and morphological structure in WGC, offering valuable insights into the development and mechanism of wax secretion in honeybees and other wax insects.

Theoretical Insight into the Palladium-Catalyzed Prenylation and Geranylation of Oxindoles with Isoprene.

This work presents a comprehensive mechanistic study of the ligand-controlled palladium-catalyzed prenylation (with C5 added) and geranylation (with C10 added) reactions of oxindole with isoprene. The calculated results indicate that the prenylation with the bis-phosphine ligand and geranylation with the monophosphine ligand fundamentally share a common mechanism. This mechanism involves the formation of two crucial species: a η3-allyl-Pd(II) cation and an oxindole carbon anion. Furthermore, the reactions necessitate the assistance of a second oxindole molecule, which serves as a Brønsted acid, providing a proton to generate the oxindole nitrogen anion. The oxindole nitrogen anion then acts as a Brønsted base, abstracting a C-H proton from another oxindole molecule to form an oxindole carbon anion. These mechanistic details differ significantly from those proposed in the experimental work. The present calculations do not support the presence of the Pd-H species and the η3, η3-diallyl-Pd(II) intermediate, which were previously suggested in experiments. The theoretical results rationalize the experimental finding that the bis-phosphine ligand favors the prenylation of oxindole, while the monophosphine ligand enables the geranylation of oxindole.

Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis.

Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.

Two in one: aluminum porphyrin-based porous organic polymers containing symmetrical quaternary phosphonium salts for catalytic conversion of CO2 into cyclic carbonates.

Based on the double activation models of epoxides, the design and synthesis of ionic porous organic polymers (iPOPs) is considered to be very attractive and promising but has remained a great challenge in recent decades owing to electrostatic interactions between charged groups. In this contribution, we developed a two-in-one strategy to fabricate metalloporphyrin-based iPOPs with unique nanostructures (named AlPor-QP@POP), which are composed of aluminum porphyrin units and three-dimensional quaternary phosphonium salts that work synergistically in the cycloaddition of CO2 with epoxides under mild conditions. The high symmetry of two monomers allows them to possess similar reactivity ratios and thus endows AlPor-QP@POP with densely located active sites, a large surface area and good CO2 capture capacity. More importantly, bifunctional AlPor-QP@POP has enormous potential to produce cyclic carbonates with simulated flue gas under ambient conditions. Moreover, AlPor-QP@POP can be readily recycled and efficiently reused more than ten times without an obvious decrease in catalytic activity. Finally, kinetic investigations and a comparative study have been conducted to understand the possible mechanism of CO2 catalytic cycloaddition.

Clinical Characteristics and Outcomes of Prolactinomas in Children and Adolescents: A Large Retrospective Cohort Study.

PURPOSE: To summarize the clinical features, both medication and surgical outcomes of prolactinomas in children and adolescents in a large retrospective cohort from China. METHODS: A cohort of patients with prolactinomas aged ≤20 years at diagnosis between 2012 and 2021 in Peking Union Medical College Hospital were retrospectively analyzed. RESULTS: The cohort comprised 170 patients (115 females and 55 males, median age 16.6 years), with 20.0% (23/115) girls without menarche and 33.3% (18/54) boys in prepuberty. The median maximal diameter was 15.0 mm (61.2% macroadenomas and 4.6% giant adenomas), and the median baseline prolactin (PRL) level was 211.0 ng/mL. Larger sizes and higher PRL levels were observed in girls without menarche at diagnosis and in boys. Most girls presented with menstrual disturbance (86.7%), and boys were frequently bothered by headaches (42.6%), reduced height velocities (25.9%), and delayed puberty (18.2%). Dopamine agonists (DAs) were first-line used in 133 patients, and the resistance rate was 22.5% (25/111), independently associated with maximal tumor diameters (p=0.035). Surgery was performed in 76 patients. Long-term surgical remission rates were 32.9% (25/76) overall, negatively associated with cavernous sinus invasion independently (p=0.025), 59.4% (19/32) in noninvasive tumors (64.0% in 25 noninvasive macroadenomas), and 5.0% (1/20) in invasive tumors. CONCLUSIONS: Pediatric prolactinomas exihibited more severe clinical characteristics in boys and in patients diagnosed during earlier stages of pubertal developments. Given the overall efficacy of PRL normalization by medication and considerable surgical remission rate in noninvasive tumors, DAs remain first-line recommendation for prolactinomas in children and adolescents, while surgery might be viable for noninvasive tumors.

Hostile attribution bias's role in perceived stress among college freshman students: A latent growth modelling approach.

This study's objective was to examine the growth trajectories of freshman students' perceived stress and whether hostile attribution bias predicts the pattern of perceived stress change using latent growth analyses. A longitudinal dataset with fourth measurement points was gathered from a total of 1109 college students enrolled at a university in Guizhou Province in the first 3 months after college freshmen enrollment. The freshman students' levels of perceived stress tend to show a piecewise linear decline during the transition period, which manifests as a faster decline in the first stage (within the first month) than in the second stage (after the first month). Moreover, hostile attribution bias not only positively predicted the initial level of perceived stress but also positively predicted the slope of perceived stress in the first and second stages. In addition, there was a significant sex difference in the initial level of perceived stress where the initial level of perceived stress was higher in females than in males, but there was no significant sex difference in the rate of perceived stress decline. These results highlight the longitudinal relationship between hostile attribution bias and perceived stress and have implications for improving freshmen' college adaptation.

Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

In Situ Anchoring of Small-Sized Silver Nanoparticles on Porphyrinic Triazine-Based Frameworks for the Conversion of CO2 into α-Alkylidene Cyclic Carbonates with Outstanding Catalytic Activities under Ambient Conditions.

The preparation of catalytic hybrid materials by introducing highly dispersed metallic nanoparticles into porous organic polymers (POPs) may be an ideal and promising strategy for integrated CO2 capture and conversion. In terms of the carboxylative cyclization of propargyl alcohols with CO2, the anchoring of silver nanoparticles (AgNPs) on functional POPs to fabricate efficient heterogeneous catalysts is considered to be quite intriguing but remains challenging. In the contribution, well-dispersed AgNPs were successfully anchored onto the porphyrinic triazine-based frameworks by a simple "liquid impregnation and in situ reduction" strategy. The presence of N-rich dual active sites, porphyrin and triazine, which acted as the electron donor and acceptor, respectively, offered a huge opportunity for the nucleation and growth of metal nanoparticles. Significantly, the as-prepared catalyst Ag/TPP-CTF shows excellent catalytic activity (up to 99%) toward the carboxylative cyclization of propargyl alcohols with CO2 at room temperature, achieving record-breaking activities (TOF up to 615 h-1 at 1 bar and 3077 h-1 at 10 bar). Moreover, the catalyst can be easily recovered and reused at least 10 times with retention of high catalytic activity. The possible mechanism involves small-sized AgNP-mediated alkyne activation, which may promote highly efficient and green conversion of CO2. This work paves the way for immobilizing metal nanoparticles onto functional POPs by surface structure changes for enhanced CO2 catalysis.

LptM promotes oxidative maturation of the lipopolysaccharide translocon by substrate binding mimicry.

Insertion of lipopolysaccharide (LPS) into the bacterial outer membrane (OM) is mediated by a druggable OM translocon consisting of a ß-barrel membrane protein, LptD, and a lipoprotein, LptE. The ß-barrel assembly machinery (BAM) assembles LptD together with LptE at the OM. In the enterobacterium Escherichia coli, formation of two native disulfide bonds in LptD controls translocon activation. Here we report the discovery of LptM (formerly YifL), a lipoprotein conserved in Enterobacteriaceae, that assembles together with LptD and LptE at the BAM complex. LptM stabilizes a conformation of LptD that can efficiently acquire native disulfide bonds, whereas its inactivation makes disulfide bond isomerization by DsbC become essential for viability. Our structural prediction and biochemical analyses indicate that LptM binds to sites in both LptD and LptE that are proposed to coordinate LPS insertion into the OM. These results suggest that, by mimicking LPS binding, LptM facilitates oxidative maturation of LptD, thereby activating the LPS translocon.

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features.

Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.

Can green finance promote green technology innovation in enterprises: empirical evidence from China.

Green technology innovation is a crucial step in China's transition towards a green economy and has received substantial financial support through green finance. However, China's efficacy in using green finance to serve enterprise green technology innovation is still at an exploratory stage. This study takes the 2017 policy of the Chinese government on "Green Finance Reform and Innovation Pilot Zones" as a quasi-natural experiment and constructs a difference-in-difference model to examine the impact of green finance on enterprise green technology innovation. The research results reveal that green financial policies significantly promote green technology innovation and have an incentive effect on the application of green invention patents and green utility model patents, with this conclusion being robust. This is particularly true for large-scale enterprises, state-owned enterprises, and non-heavy polluting enterprises. Compared to large-scale enterprises, state-owned enterprises, and non-heavy-polluting enterprises are more inclined to apply for green invention patents. Inspection of influence mechanisms suggests that green finance policies alleviate financing constraints and signaling effect to improve enterprises' green innovation, whereas external market supervision is ineffective. Based on empirical results, relevant policy suggestions are proposed to help green finance better serve enterprises' green innovation.

Patients with dermatomyositis shared partially similar transcriptome signature with COVID-19 infection.

Dermatomyositis (DM) is an autoimmune disease that primarily affects the skin and skeletal muscle. Virus infection and type I interferon-related signaling pathways play an important role in the pathogenesis of dermatomyositis. In this study, we found that the skin of patients with DM and the skin of patients with COVID-19 have similar transcriptional profiles, and identified key genes involved in dermatomyositis based on bioinformatics analysis. These hub-genes might be served as potential biomarkers for the early diagnosis and therapy of DM, including MX1, ISG15, IFIT3, IFIT1, RSAD2, IFIT2, IFI6, XAF1, IRF9, MX2.

EZH2 inhibition dampens autoantibody production in lupus by restoring B cell immune tolerance.

OBJECTIVE: The aim of this study was to elucidate the role of enhancer of zeste homolog 2 (EZH2) in the breakdown of B cell immune tolerance and production of autoantibodies in systemic lupus erythematosus (SLE), and to explore the therapeutic effects of EZH2 inhibition on lupus. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from new-onset SLE patients for flow cytometric analysis. Pristane-induced lupus mice were constructed, and the EZH2 inhibitor was administrated by intraperitoneal injection to treat lupus mice. Blood and urine were collected from lupus mice to detect autoantibodies and proteinuria, and renal pathology scores were assessed. Mouse spleen B cells were sorted with magnetic beads and subjected to flow cytometric apoptosis detection, real time quantitative PCR (RT-qPCR), and western blotting (WB). RESULTS: EZH2 expression was elevated in diverse B-cell subsets in both SLE patients and pristane-induced lupus mice. The EZH2 inhibitor attenuated lupus-like symptoms and dampened autoantibody production in pristane-induced lupus mice. Inhibition of EZH2 also reduced autoantibody secretion by plasma cells from lupus patients. Mechanistically, EZH2 mediated the impaired apoptosis of autoreactive B cells and the differentiation of autoantibody producing plasma cells by inhibiting multiple cyclin-dependent kinase inhibitor (CKI) genes. CONCLUSION: EZH2 mediated the breakdown of B-cell peripheral immune tolerance by inhibiting CKI genes and participated in the generation of autoantibodies in SLE. EZH2 inhibition could serve as a promising drug intervention for the treatment of SLE.