Nuclear receptor 4A1 ameliorates renal fibrosis by inhibiting vascular endothelial growth factor A induced angiogenesis in UUO rats.

INTRODUCTION: Angiogenesis is closely related to renal fibrosis; however, its basic mechanism remains unclear. In our study, we found that nuclear receptor 4A1 (NR4A1) inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenesis, ameliorating renal fibrosis. METHODS: We prepared a renal fibrosis animal model with unilateral ureteral obstruction (UUO) and NR4A1 knockdown UUO mice model, Using Human umbilical vein endothelial cells (HUVECs) to conduct all in vitro experiments. We then detected and analyzed the expression levels of NR4A1 and other genes related to angiogenesis and fibrosis. RESULTS: The angiogenesis related genes, such as VEGFA, vascular endothelial growth factor receptor-2 (VEGFR-2), endoglin (CD105), as well as the expression of fibrosis related genes that included, α-smooth muscle actin (α-SMA), Vimentin, and Collagen I are all significantly increased in the UUO rat model. In addition, the expression of NR4A1 of the kidney tissue of UUO rats was significantly reduced. Therefore, according to the above results, we speculated that angiogenesis may exacerbate renal fibrosis and NR4A1 may repress renal fibrosis by inhibiting angiogenesis. To further verify the above results, we used VEGFA to stimulate HUVECs with (or without) overexpression or knockdown of NR4A1. The results showed that with prolonged stimulation using VEGFA, the expression of NR4A1 decreases. Overexpression of NR4A1 significantly inhibits the expression of related indicators of angiogenesis and renal fibrosis. Furthermore, knockdown of NR4A1 induces endothelial cell proliferation and migration; therefore, exacerbating angiogenesis and fibrosis. Finally, the results of NR4A1 knockdown UUO mice showed that knockdown of NR4A1 can aggravating kidney damage and induce the expression of angiogenesis and renal fibrosis related indicators, while UUO can significantly induce kidney damage, angiogenesis and renal fibrosis. When knockdown of NR4A1, renal kidney damage, angiogenesis and fibrosis becomes more severe than UUO. Thus, all of these results indicate that NR4A1 can ameliorate renal fibrosis by inhibiting angiogenesis. CONCLUSIONS: NR4A1 can inhibit angiogenesis to ameliorate renal fibrosis.

Inhibitory effects of Eplerenone on angiogenesis via modulating SGK1/TGF-ß pathway in contralateral kidney of CKD pregnancy rats.

BACKGROUND: Eplerenone is a selective aldosterone receptor blocker that is effective in preventing the progression of chroinic kidney disease (CKD). However, its mechanism and role in CKD pregnancy still remain uncertain. The aim of this study was to evaluate whether eplerenone could attenuated the fibrosis of unilateral ureteral obstruction (UUO) pregnant rats' contralateral kidney, improved pregnancy outcome and explore its therapeutic mechanisms. METHODS: A pregnancy rat model of UUO established, female Wistar rats were randomly assigned into sham-operated group (Sham group),sham-operated combined pregnancy group (SP group), unilateral ureteral obstruction combined pregnancy group (UUO + Pregnancy group), unilateral ureteral obstruction combined pregnancy, administered eplerenone (UUO + Pregnancy+Eplerenone group). On the 18th day of pregnancy, the rats were placed in a metabolic cage, 24 h urine was collected and stored at -80 °C. Next day, all animals were euthanized, and serum was collected by centrifugation and stored at -20 °C. Then the right kidney was extracted, a part of the kidney was placed in 4% paraformaldehyde for morphology, immunohistochemical staining, and immunofluorescence staining, and the other part was placed in a - 80 °C refrigerator for RNA and protein extraction. In vitro, HUVECs was treated with aldosterone, progesterone and estradiol, VEGFA and its receptor blocker bevacizumab. The ability of proliferation, migration and tubularization of HUVECs was detected by CCK-8, scratch wound assay and endothelial tube formation assay. And the co-expression of CD34 and α-SMA of HUVECs was detected by Flow cytometry. RESULTS: Immunofluorescence results showed that the co-expression of CD34 and α-SMA increased in the UUO + Pregnancy group was significantly increased. The expression of SGK-1, TGFß-1, Smad2, Smad3, VEGF-A, VEGFR2, CD34, α-SMA and Collagen I was significantly higher in the kidneys of the UUO + Pregnancy group compared to the Sham group and SP group. Eplerenone inhibited the expression of those results. In vitro, the ability of proliferation, migration and tubularization was increased after treated with aldosterone, aldosterone with progesterone and estradiol or VEGFA. Similarly, the expression of α-SMA on the surface of HUVECs treated with aldosterone, aldosterone with progesterone and estradiol were increased, while eplerenone supressed its expression. CONCLUSION: Eplerenone inhibits renal angiogenesis by blocking the SGK-1/TGFß signal transduction pathway, thereby inhibiting the phenotypic transformation of endothelial cells, slowing down renal fibrosis, and reducing kidney damage caused by pregnancy.

Janus liposozyme for the modulation of redox and immune homeostasis in infected diabetic wounds.

Diabetic foot ulcers often become infected, leading to treatment complications and increased risk of loss of limb. Therapeutics to manage infection and simultaneously promote healing are needed. Here we report on the development of a Janus liposozyme that treats infections and promotes wound closure and re-epithelialization. The Janus liposozyme consists of liposome-like selenoenzymes for reactive oxygen species (ROS) scavenging to restore tissue redox and immune homeostasis. The liposozymes are used to encapsulate photosensitizers for photodynamic therapy of infections. We demonstrate application in methicillin-resistant Staphylococcus aureus-infected diabetic wounds showing high ROS levels for antibacterial function from the photosensitizer and nanozyme ROS scavenging from the liposozyme to restore redox and immune homeostasis. We demonstrate that the liposozyme can directly regulate macrophage polarization and induce a pro-regenerative response. By employing single-cell RNA sequencing, T cell-deficient Rag1-/- mice and skin-infiltrated immune cell analysis, we further reveal that IL-17-producing γδ T cells are critical for mediating M1/M2 macrophage transition. Manipulating the local immune homeostasis using the liposozyme is shown to be effective for skin wound repair and tissue regeneration in mice and mini pigs.

The relationship and clinical significance of serum cytokine expression level and skin pruritus in patients with Hodgkin lymphoma and angioimmunoblastic T-cell lymphoma.

Pruritus of lymphoma is commonly associated with both Hodgkin lymphoma (HL) and angioimmunoblastic T cell lymphoma (AITL) and critically affects the life quality of patient. Recent evidence suggests that the pruritogenic cytokines seem to play a significant role in the genesis of chronic. This study aims to investigate the cytokines associated with itching in lymphoma patients and provide the basis for potential therapeutic targets. Serum samples were collected from 60 lymphoma patients, including 47 with Hodgkin lymphoma (HL) and 13 with angioimmunoblastic T-cell lymphoma (AITL), serving as the observation group (lymphoma group, LP group, n = 60). Additionally, serum samples from 8 healthy donors (HD group, n = 8) were collected for comparison. Within the lymphoma group, patients were stratified into those with pruritus (LWP group, n = 30) and those without pruritus (LWOP group, n = 30) based on the presence of skin pruritus symptoms. Elevated levels of multiple cytokines were significantly observed in the LP group in comparison to the HD group (p < 0.01). Patients in LWP group exhibited higher serum levels of IL-31 (p < 0.001), IL-1ß (P = 0.039), and IL-1α (P = 0.037) compared to LWOP group. Notably, serum IL-31 levels were higher in advanced AITL patients (stage IV) than in early AITL patients (stage I-Ⅲ, P < 0.05). In subgroup analysis, patients with pruritus in the AITL group exhibited higher serum levels of MIG and CTACK compared to HL group, whereas PDGF-BB levels were significantly lower (p < 0.05). Elevated serum levels of IL-31, IL-1ß, and IL-1α are linked to lymphoma-associated pruritus. Differences in serum cytokine profiles between HL and AITL subgroups are also highlighted. These findings offer valuable insights for clinical intervention in managing lymphoma-related pruritus.

RNA Seq and ceRNA Network Analysis of the Rat Model of Chronic Kidney Disease.

BACKGROUND: Long non-coding RNAs (lncRNAs) containing microRNA (miRNA) response elements (MREs) can be used as competitive endogenous RNAs (ceRNAs) to regulate gene expression. OBJECTIVE: The purpose of this study was to investigate the expression profile and role of mRNAs and lncRNAs in unilateral ureteral obstruction (UUO) model rats and to explore any associated competing endogenous (ceRNA) network. METHODS: Using the UUO model, the obstructed kidney was collected on the 15th day after surgery. RNA Seq analysis was performed on renal tissues of four UUO rats and four sham rats. Four mRNAs and four lncRNAs of differentially expressed genes were randomly selected for real-time quantitative PCR (RT qPCR) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed, and bioinformatics was used to predict MREs. By screening for ceRNAs combined with target gene prediction, a related ceRNA network was constructed and verified by RT-qPCR. RESULTS: We identified 649 up-regulated lncRNAs, 518 down-regulated lncRNAs, 924 downregulated mRNAs and 2029 up-regulated mRNAs. We identified 30 pathways with the highest enrichment in GO and KEGG. According to the RNA Seq results and the expression of Nr4a1, the network was constructed based on Nr4a1 and included two MREs and ten lncRNAs. Furthermore, lncNONRATT011668.2/miR-361-3p/Nr4a1 was identified and verified according to ceRNA sequencing and target gene prediction. CONCLUSION: mRNAs and lncRNAs are differentially expressed in UUO model rats, which may be related to the pathogenesis of chronic kidney disease. The lncNONRATT011668.2/miR-361- 3p/Nr4a1 ceRNA network may be involved in the pathogenesis of chronic kidney disease.

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4.

Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury.

The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.

A novel effector, CsSp1, from Bipolaris sorokiniana, is essential for colonization in wheat and is also involved in triggering host immunity.

The hemibiotrophic pathogen Bipolaris sorokiniana causes root rot, leaf blotching, and black embryos in wheat and barley worldwide, resulting in significant yield and quality reductions. However, the mechanism underlying the host-pathogen interactions between B. sorokiniana and wheat or barley remains unknown. The B. sorokiniana genome encodes a large number of uncharacterized putative effector proteins. In this study, we identified a putative secreted protein, CsSp1, with a classic N-terminal signal peptide, that is induced during early infection. A split-marker approach was used to knock out CsSP1 in the Lankao 9-3 strain. Compared with the wild type, the deletion mutant ∆Cssp1 displayed less radial growth on potato dextrose agar plates and produced fewer spores, and complementary transformation completely restored the phenotype of the deletion mutant to that of the wild type. The pathogenicity of the deletion mutant in wheat was attenuated even though appressoria still penetrated the host. Additionally, the infectious hyphae in the deletion mutant became swollen and exhibited reduced growth in plant cells. The signal peptide of CsSp1 was functionally verified through a yeast YTK12 secretion system. Transient expression of CsSp1 in Nicotiana benthamiana inhibited lesion formation caused by Phytophthora capsici. Moreover, CsSp1 localized in the nucleus and cytoplasm of plant cells. In B. sorokiniana-infected wheat leaves, the salicylic acid-regulated genes TaPAL, TaPR1, and TaPR2 were down-regulated in the ∆Cssp1 strain compared with the wild-type strain under the same conditions. Therefore, CsSp1 is a virulence effector and is involved in triggering host immunity.

Histone acetyltransferases MystA and MystB contribute to morphogenesis and aflatoxin biosynthesis by regulating acetylation in fungus Aspergillus flavus.

Myst family is highly conserved histone acetyltransferases in eukaryotic cells and is known to play crucial roles in various cellular processes; however, acetylation catalysed by acetyltransferases is unclear in filamentous fungi. Here, we identified two classical nonessential Myst enzymes and analysed their functions in Aspergillus flavus, which generates aflatoxin B1, one of the most carcinogenic secondary metabolites. MystA and MystB located in nuclei and cytoplasm, and mystA could acetylate H4K16ac, while mystB acetylates H3K14ac, H3K18ac and H3K23ac. Deletion mystA resulted in decreased conidiation, increased sclerotia formation and aflatoxin production. Deletion of mystB leads to significant defects in conidiation, sclerotia formation and aflatoxin production. Additionally, double-knockout mutant (ΔmystA/mystB) display a stronger and similar defect to ΔmystB mutant, indicating that mystB plays a major role in regulating development and aflatoxin production. Both mystA and mystB play important role in crop colonization. Moreover, catalytic domain MOZ and the catalytic site E199/E243 were important for the acetyltransferase function of Myst. Notably, chromatin immunoprecipitation results indicated that mystB participated in oxidative detoxification by regulating the acetylation level of H3K14, and further regulated nsdD to affect sclerotia formation and aflatoxin production. This study provides new evidences to discover the biological functions of histone acetyltransferase in A. flavus.

Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Hydrogen-rich gas production from steam co-gasification of banana peel with agricultural residues and woody biomass.

Steam co-gasification of banana peel with other biomass, i.e., Japanese cedar wood, rice husk and their mixture, was carried out for the hydrogen-rich gas production in a fixed-bed reactor. For the co-gasification process, the banana peels were physically mixed with rice husk, Japanese cedarwood and their mixture respectively by different mixing weight ratios. The effects of reaction temperature and the addition amount of banana peel on the gas production yield were investigated by comparing the experimental data with the calculated ones based on the individual biomass gasification at the same condition. It was found that the banana peel with a high content of alkali and alkaline earth metal (AAEM) species exhibited not only high gasification reactivity but also a significant enhancing catalytic effect on the co-gasification process at the low temperature, especially with the biomass containing no silica species. The high content of silica species in the rice husk had a negative effect on the gasification reactivity of banana peel during the co-gasification since it could hinder the release of AAEM from the biomass and/or lead to the possible formation of inactive alkaline silicates. However, the combination of these three samples with the suitable weight ratio could improve the gasification performance at the low temperature due to the synergetic effect provided by high contents of potassium and calcium from banana peel and cedarwood respectively. Moreover, the addition of calcined seashells as the CaO source could further improve the gas production yield, especially the hydrogen gas yield at a relatively low gasification temperature of 750 ℃.

T Cells in Fibrosis and Fibrotic Diseases.

Fibrosis is the extensive deposition of fibrous connective tissue, and it is characterized by the accumulation of collagen and other extracellular matrix (ECM) components. Fibrosis is essential for wound healing and tissue repair in response to a variety of triggers, which include infection, inflammation, autoimmune disorder, degenerative disease, tumor, and injury. Fibrotic remodeling in various diseases, such as liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD), can impair organ function, causing high morbidity and mortality. Both innate and adaptive immunity are involved in fibrogenesis. Although the roles of macrophages in fibrogenesis have been studied for many years, the underlying mechanisms concerning the manner in which T cells regulate fibrosis are not completely understood. The T cell receptor (TCR) engages the antigen and shapes the repertoire of antigen-specific T cells. Based on the divergent expression of surface molecules and cell functions, T cells are subdivided into natural killer T (NKT) cells, γδ T cells, CD8+ cytotoxic T lymphocytes (CTL), regulatory T (Treg) cells, T follicular regulatory (Tfr) cells, and T helper cells, including Th1, Th2, Th9, Th17, Th22, and T follicular helper (Tfh) cells. In this review, we summarize the pro-fibrotic or anti-fibrotic roles and distinct mechanisms of different T cell subsets. On reviewing the literature, we conclude that the T cell regulations are commonly disease-specific and tissue-specific. Finally, we provide perspectives on microbiota, viral infection, and metabolism, and discuss the current advancements of technologies for identifying novel targets and developing immunotherapies for intervention in fibrosis and fibrotic diseases.

Recycling the CoMo/Al2O3 catalyst for effectively hydro-upgrading shale oil with high sulfur content and viscosity.

Hydrotreatment is an effective upgrading technology for removing contaminants and saturating double bonds. Still, few studies have reported the hydro-upgrading of shale oil, with unusually high sulfur (13200 ppm) content, using the CoMo/Al2O3 catalyst. Here we report an extensive study on the upgrading of shale oil by hydrotreatment in a stirred batch autoclave reactor (500 ml) for sulfur removal and viscosity reduction. From a preliminary optimization of the reaction factors, the best-operating conditions were 400 °C, an initial H2-pressure of 5 MPa, and an agitation rate of 800 rpm, a catalyst-to-oil ratio of 0.1, and a reaction time of 1 h. We could achieve a sulfur removal efficiency of 87.1% and 88.2% viscosity reduction under the optimal conditions. After that, the spent CoMo/Al2O3 was repeatedly used for subsequent upgrading tests without any form of pre-treatment. The results showed an increase in the sulfur removal efficiency with an increase in the number of catalyst runs. Ultimately, 99.5-99.9% sulfur removal from the shale oil was achieved by recycling the spent material. Both the fresh and the spent CoMo/Al2O3 were characterized and analyzed to ascertain their transformation levels by XRD, TEM, TG, XPS, TPD and N2 adsorption analysis. The increasing HDS efficiency is attributed to the continuing rise in the sulfidation degree of the catalyst in the sulfur-rich shale oil. The light fraction component in the liquid products (IBP-180 °C) was 30-37 vol% higher than in the fresh shale oil. The product oil can meet the sulfur content requirement of the national standard marine fuel (GB17411-2015/XG1-2018) of China.

miR-34b/c regulates doxorubicin-induced myocardial cell injury through ITCH.

Objective: To determine the underlying mechanism of miR-34b/c in regulating doxorubicin (Dox)-induced myocardial cell injury.Methods: The viability of mouse myocardial cells HL-1 was detected by MTT assay. The apoptosis of HL-1 cells was detected by TUNEL assay. mRNA expressions of ITCH, TNF-α and IL-6 were measured by qRT-PCR. Protein levels of ITCH, NF-κB, TNF-α and IL-6 were measured by western blot. Dual luciferase assay was performed to detect the regulation of miR-34b/c on ITCH. Mouse model of cardiomyopathy was induced by intraperitoneal injection of Dox.Results: Dox reduced HL-1 cell viability and activated NF-κB pathway in HL-1 cells. miR-34b/c expressions were gradually up-regulated and ITCH expression was gradually down-regulated in Dox-treated HL-1 cells. miR-34b/c expression had negative correlation with the mRNA expression of ITCH. Besides, ITCH was a target of miR-34b/c. miR-34b/c mimic reduced cell viability, suppressed ITCH expression, increased TNF-α and IL-6 level, and promoted NF-κB expression in nucleus and cytoplasm of HL-1 cells. Whereas silencing miR-34 protected HL-1 cells through regulating ITCH. Finally, we demonstrated miR-34 antagomir-protected myocardial cells in mouse model of cardiomyopathy.Conclusion: miR-34b/c decreased HL-1 cell viability and promoted the secretion of proinflammatory cytokines in Dox-induced myocardial cells through ITCH/NF-κB pathway.

Reaction condition controlled nickel(ii)-catalyzed C-C cross-coupling of alcohols.

The challenge in the C-C cross-coupling of secondary and primary alcohols using acceptorless dehydrogenation coupling (ADC) is the difficulty in accurately controlling product selectivities. Herein, we report a controlled approach to a diverse range of ß-alkylated secondary alcohols, α-alkylated ketones and α,ß-unsaturated ketones using the ADC methodology employing a Ni(ii) 4,6-dimethylpyrimidine-2-thiolate cluster catalyst under different reaction conditions. This catalyst could tolerate a wide range of substrates and exhibited a high activity for the annulation reaction of secondary alcohols with 2-aminobenzyl alcohols to yield quinolines. This work is an example of precise chemoselectivity control by careful choice of reaction conditions.

RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer.

BACKGROUND: The mechanisms of breast cancer collective invasion are poorly understood limiting the metastasis therapy. The ATPase RUVBL1 is frequently overexpressed in various cancers and plays a crucial role in oncogenic process. We further investigated the role of RUVBL1 in promoting collective invasion and uncovered that targeting RUVBL1 could inhibit metastatic progression. METHODS: The expression levels of RUVBL1 and ITFG1 were examined by Western blot and qRT-PCR. Co-localization and interaction of RUVBL1 and ITFG1 were determined by immunofluorescence and co-immunoprecipitation. The invasive ability was examined by transwell assay and microfluidic assay. The metastatic and tumorigenic abilities of breast cancer cells were revealed in BALB/c nude mice by xenograft and tail vein injection. RESULTS: ATPase RUVBL1 is highly expressed in breast cancer and predicts the poor prognosis. Elevated expression of RUVBL1 is found in high metastatic breast cancer cells. Silencing RUVBL1 suppresses cancer cell expansion and invasion in vitro and in vivo. RUVBL1 interacts with a conserved transmembrane protein ITFG1 in cytoplasm and plasma membrane to promote the collective invasion. Using a microfluidic model, we demonstrated that silencing RUVBL1 or ITFG1 individually compromises collective invasion of breast cancer cells. CONCLUSION: RUVBL1 is a vital regulator for collective invasion. The interaction between RUVBL1 and ITFG1 is required for breast cancer cell collective invasion and progression. GENERAL SIGNIFICANCE: Targeting collective invasion promoted by RUVBL1-ITFG1 complex provides a novel therapeutic strategy to improve the prognosis of invasive breast cancer.