Search

PDF file - 668K, HAb18G/CD147 knock-down efficiency and function validation (related to Figure 1).

PDF file - 397K, HAb18G/CD147, pSTAT3 and survivin levels in a panel of human pancreatic cancer cell lines (related to Figure 1, 2A).

Purpose: Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo.Experimental Design: The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies.Results: Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer.Conclusions: We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies. Clin Cancer Res; 19(24); 6703–15. ©2013 AACR.

PDF file - 112K, The sequences of the oligonucleotide primers used for qPCR (related to the qRT-PCR section of Materials and Methods).

PDF file - 30K, The effect of Sp1 and c-Myc overexpression or knockdown on CD147 expression detecting by western blot.

PDF file - 37K, Luciferase assays the effect of Sp3 and Sp4 on CD147 transcription regulation.

PDF file - 44K, The expression of miR-22 in breast cancer tissues.

PDF file - 96K, Clinicopathologic characteristics of miR-22 expression in breast cancer patients.

PDF file - 78K

PDF file - 17K, Western blot assays the effect of Sp3 and Sp4 on CD147 protein expression.

PDF file - 103K

PDF file - 61K, Luciferase assays the effect of miR-22 on Sp3 and Sp4 post-transcriptional regulation.

PDF file - 75K, Oligonucleotide sequence of PCR primers and siRNA fragments.

PDF file - 71K, Luciferase assays the effect of Sp3 and Sp4 on miR-22 transcription regulation.

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 + T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 + T cell responses and autoantibody production in autoimmune diseases.

Regulatory T cell (Treg) stability is necessary for the proper control of immune activity and tissue homeostasis. However, it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions. Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability. Here, we demonstrate that to maintain Foxp3 protein expression, Tregs require cell-to-cell contact, which is mediated by the CD147-CD98 interaction. As Tregs are produced, CD147, which is expressed on their surface, is stimulated by CD98, which is widely expressed in the physiological environment. As a result, CD147’s intracellular domain binds to CDK2 and retains it near the membrane, leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation. In addition, the optimal distribution of Foxp3+ Tregs under both pathological and physiological conditions depends on CD98 expression. Thus, our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment. More importantly, Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability, which has guiding significance for the application of Tregs in immunotherapy.

The prosperity of the biotherapeutics market reflects the feasibility and effectiveness of therapeutic antibodies for the treatment of cancers, inflammatory disorders, and refractory infections. As drawbacks emerge in clinical trials and practice, such as impeded binding, reduced effector functions, and frequent adverse reactions, modifications of therapeutic antibodies are unprecedently burgeoning in research and development (R&D). These modifications include: ① modified glycosylation; ② fragment of crystallizable domain (Fc) amino acid alterations; ③ cross-isotype or cross-subclass exchanges; ④ antibody–drug conjugates (ADCs); ⑤ single chain of variable region fragment (scFv) for chimeric antigen receptor T (CAR-T) cells; and ⑥ bispecific antibodies (bsAbs) in order to promote binding affinity, half-life in circulation, effectiveness toward target cells and, ultimately, to achieve overall improved efficacy. While many achievements have been made around the world in the past decades, China has been playing an active role in this realm, with its great demand for biotherapeutics with R&D potential. This review recapitulates the international progress that has been achieved with modified therapeutic antibodies, and then focuses on that of China in an independent section.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines represent a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents including anti-PD-1 and immune adjuvant poly I:C may be combined with DC vaccines to further enhance antitumor activity. Here we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-PD-1 and poly I:C as well as a chemotherapeutic agent cyclophosphamide that were integrated with the standard chemoradiation therapy for > 5 years. The patient who received DC vaccines loaded with multiple forms of tumor antigens including mRNA-tumor associated antigens (TAAs), mRNA-neoantigens, and hypochlorous acid-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology which fuses TAAs with a destabilization domain and inserts TAAs into a full-length LAMP-1 to enhance MHC class I and II antigen presentation, respectively. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy related adverse events were observed during the treatment. Robust anti-tumor CD4+ and CD8+ T cell responses were detected. The patient remains free of disease progression as of July, 2022. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment. A large scale trial to validate these findings is warranted. Protocol numbers: 201708152377, 20202014-F-1

This prospective non-randomized, multicenter clinical trial was performed to investigate efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 months in the TACE+131I-metuximab group (n = 160) and 3 months in the TACE group (n = 160) (hazard ratio, 0.55; 95% confidence interval, 0.43 to 0.70; P < 0.001). The median overall survival was 28 months in the TACE+131I-metuximab group and 19 months in the TACE group (hazard ratio, 0.62; 95% confidence interval, 0.47 to 0.82; P = 0.001). Conclusion: TACE+131I-metuximab showed a greater anti-recurrence benefit, significantly improved the 5-year survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

Sepsis is a life‐threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)‐ or caecal ligation and puncture (CLP)‐induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro‐inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti‐oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti‐oxidative enzymes including NQO‐1, GST, HO‐1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin‐induced Nrf2 activation could suppress NF‐κB‐regulated up‐regulation of pro‐inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti‐oxidative enzymes and inhibited NF‐κB‐regulated pro‐inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.

Aims The blood‐brain barrier (BBB) is a specialized and indispensable structure in brain blood vessels that is damaged during Alzheimer's disease (AD). CD147 is expressed on the BBB and deeply engaged in the AD pathological process. In this study, we aimed to provide a better understanding of the roles of CD147 in BBB function in health and neurodegenerative disease. Methods and Results We measured CD147 expression in mouse brains and demonstrated that CD147 is exclusively expressed in brain endothelial cells (BECs), and its expression decreases with age. After constructing endothelial‐specific CD147 knockout mice, we performed RNA‐sequencing on BECs isolated from mice of different ages as well as a range of database analyses. We found that endothelial CD147 is essential for the dual functions of the BBB, including barrier maintenance and transporter regulation. This study also shows that CD147 plays a pivotal role in neurodegenerative diseases, particularly in AD. Conclusions Our findings suggested that targeting CD147 in BECs may represent a novel therapeutic strategy, which promoted the design of future experimental investigations and the mechanistic understanding of neurodegenerative diseases., Mouse primary brain endothelial cells isolated from endothelial‐specific CD147 knockout mice of different ages were performed RNA‐sequencing. CD147 is essential for the dual functions of the blood‐brain barrier, including barrier maintenance and transporter regulation, and neurodegenerative diseases, particularly Alzheimer's disease.

sRecent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood–pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Negative regulation of antitumor T-cell-immune responses facilitates tumor-immune escape. Here, we show that deletion of CD147, a type I transmembrane molecule, in T cells, strongly limits in vivo tumor growth of mouse melanoma and lung cancer in a CD8+ T-cell-dependent manner. In mouse tumor models, CD147 expression was upregulated on CD8+ tumor-infiltrating lymphocytes (TILs), and CD147 was coexpressed with two immune-checkpoint molecules, Tim-3 and PD-1. Mining publicly available gene-profiling data for CD8+ TILs in tumor biopsies from metastatic melanoma patients showed a higher level of CD147 expression in exhausted CD8+ TILs than in other subsets of CD8+ TILs, along with expression of PD-1 and TIM-3. Additionally, CD147 deletion increased the abundance of TILs, cytotoxic effector function of CD8+ T cells, and frequency of PD-1+ CD8+ TILs, and partly reversed the dysfunctional status of PD-1+Tim-3+CD8+ TILs. The cytotoxic transcription factors Runx3 and T-bet mediation enhanced antitumor responses by CD147-/- CD8+ T cells. Moreover, CD147 deletion in T cells increased the frequency of TRM-like cells and the expression of the T-cell chemokines CXCL9 and CXCL10 in the tumor microenvironment. Analysis of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8+ TILs and the abundance of CD8+ TILs, histological grade of the tumor tissue samples, and survival of patients with advanced tumors. Altogether, we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8+ TILs and identified CD147 as a potential target for cancer immunotherapy.

Nonalcoholic fatty liver disease (NAFLD) represents a global health problem. Impaired autophagy has been implicated in the pathogenesis of NAFLD, and CD147 is recognized to regulate lipid metabolism in a variety of cell types. This study was initiated with the aim to identify molecular makers expressed in hepatocytes that are significantly altered during the pathogenesis of NAFLD and closely associated with hepatic steatosis and autophagy. In this study, CD147 was found to be significantly associated with steatosis and autophagy in both clinical patients with NAFLD and NAFLD mouse models. In high-fat-diet-induced NAFLD mice, hepatic-specific CD147 knockout markedly reduced body weight, liver weight, serum aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), and liver steatosis. In addition, hepatic CD147 gene knockout noticeably promoted autophagy in NAFLD mice (LC3 expression was increased with decreased P62 expression; molecular markers of autophagy). Moreover, we found that CD147 expression was significantly associated with AKT/mTOR signaling pathway; thus, suggesting that CD147 is involved in the regulation of autophagy and steatosis in NAFLD. In conclusion, this study has provided in vivo evidence for the putative role of CD147 in the pathogenesis of NAFLD and a valuable experimental basis for considering CD147 as a therapeutic target to prevent hepatic steatosis in patients with NAFLD.

Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity. Here, we show that the loss of CD147 on T cells prevents thymic senescence, resulting in slowed shrinkage of the thymus with age and increased production of naive T cells. This phenotype is the result of slowing of the epithelial–mesenchymal transition (EMT) process in thymic epithelial cells (TECs), which eventually leads to reduced adipocyte accumulation. In an in vitro coculture system, we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-Smad2/FoxC2 signaling. Moreover, CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs. In the presence of TGFβ, Annexin A2 and E-cadherin colocalize on TECs. However, CD147 on T cells competitively binds to Annexin A2 on TECs, leading to the isolation of E-cadherin. Then, the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase, the phosphorylation of which was induced by TGFβ, and finally, p-E-cadherin is degraded. Thus, in the thymus, the interaction between T cells and TECs contributes to thymic involution with age. In this study, we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.

Acetyl-CoA carboxylase (ACC) is one of the more promising therapeutic targets for non-alcoholic steatohepatitis (NASH), but current ACC inhibitors already tested in clinical trials also exert the unwanted adverse side effect of hypertriglyceridemia. In two recent studies by Calle et al. in Nature Medicine and Zhang et al. in Science Translational Medicine, new strategies for ACC targeting were explored for NASH therapy that successfully resolved the adverse effect of hyperlipidemia while maintaining potent anti-NASH efficacy. These findings bring encouraging new momentum to the clinical application of ACC inhibition for NASH therapy.

T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkdc

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

Non-small cell lung cancer (NSCLC) is a fatal disease, and its metastatic process is poorly understood. Although aberrant methylation is involved in tumor progression, the mechanisms underlying dynamic DNA methylation remain to be elucidated. It is significant to study the molecular mechanism of NSCLC metastasis and identify new biomarkers for NSCLC early diagnosis. Here, we performed MeDIP-seq and hMeDIP-seq analyses to detect the genes regulated by dynamic DNA methylation. Comparison of the 5mC and 5hmC sites revealed that the CD147 gene underwent active demethylation in NSCLC tissues compared with normal tissues, and this demethylation upregulated CD147 expression. Significantly high levels of CD147 expression and low levels of promoter methylation were observed in NSCLC tissues. Then, we identified the CD147 promoter as a target of KLF6, MeCP2, and DNMT3A. Treatment of cells with TGF-β triggered active demethylation involving loss of KLF6/MeCP2/DNMT3A and recruitment of Sp1, Tet1, TDG, and SMAD2/3 transcription complexes. A dCas9-SunTag-DNMAT3A-sgCD147-targeted methylation system was constructed to reverse CD147 expression. The targeted methylation system downregulated CD147 expression and inhibited NSCLC proliferation and metastasis in vitro and in vivo. Accordingly, we used cfDNA to detect the levels of CD147 methylation in NSCLC tissues and found that the CD147 methylation levels exhibited an inverse relationship with tumor size, lymphatic metastasis, and TNM stage. In conclusion, this study clarified the mechanism of active demethylation of CD147 and suggested that the targeted methylation of CD147 could inhibit NSCLC invasion and metastasis, providing a highly promising therapeutic target for NSCLC.

Major gaps in understanding the molecular mechanisms of colorectal cancer (CRC) progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders. Trefoil factor 3 (TFF3) has been reported to be involved in CRC progression and intestinal mucosal repair; however, how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood. Here, we found that the upregulated TFF3 in CRC predicted a worse overall survival rate. TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis. CD147, a membrane protein, was identified as a binding partner for TFF3. Via binding to CD147, TFF3 enhanced CD147-CD44s interaction, resulting in signal transducer and activator of transcription 3 (STAT3) activation and prostaglandin G/H synthase 2 (PTGS2) expression, which were indispensable for TFF3-induced migration, proliferation, and invasion. PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype (PTGER4) and contributed to TFF3-stimulated CRC progression. Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression. The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor. Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice. Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression, which widens and deepens the understanding of the molecular function of trefoil factors.

The γ-secretase complex is a presenilin-dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ-secretase complex inhibitor and CD147-directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ-secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Ankylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive. Methods Utilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities. Findings We found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease. Interpretation These results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development.

Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer1,2. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger ferroptosis3. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase4–7. Counterintuitively, mesenchymal cancer cells—which are prone to metastasis, and often resistant to various treatments—are highly susceptible to ferroptosis8,9. Here we show that ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis8. Notably, a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma10,11, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2–YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2–YAP signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies. Ferroptosis in cancer cells can be regulated by cadherin-mediated intercellular contacts, NF2–Hippo signalling, and activity of the YAP transcription co-activator.

Receptor-interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid-derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma-positive (IFN-γ+ ) cluster of differentiation 8-positive (CD8+ ) tumor-infiltrating lymphocytes (IFN-γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1-chemokine (C-X-C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2-induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1-CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.

Cluster of differentiation 147 (CD147), a transmembrane protein of the immunoglobulin superfamily, is a potential target of treatment against human non-small cell lung cancer (NSCLC). Although there have been exciting advances in epidermal growth factor receptor (EGFR)-targeted therapy for NSCLC in recent years, additional novel targeted agents are needed to improve the efficiency and to offer more options for patients. Antibody-drug conjugates (ADCs) utilize a chemical linker to conjugate cytotoxic drugs to a monoclonal antibody to maximize the delivery to target cells and minimize the delivery to other normal cells. The aim of this study was to prepare a novel anti-CD147 conjugate and examine the tumoricidal effect on NSCLC in vitro and in vivo. HcHAb18 was conjugated to the drug maytansinoid 1 (DM1) via a non-cleavable thioether linker (SMCC) to prepare HcHAb18-DM1 with an appropriate drug-antibody ratio (DAR). NSCLC cell lines expressing different levels of CD147 were tested in vitro to determine internalization, cell cycle arrest and cytotoxicity. In vivo efficacy and safety of HcHAb18-DM1 were evaluated in NSCLC xenograft mouse models. We found that HcHAb18-DM1 displayed an impressive potency in vitro and in vivo with a favorable safety profile. Upon binding to CD147, HcHAb18 could be internalized and delivered the payload DM1 to disturb mitotic spindle formation by microtubules. Target cells were arrested at G2/M phase and HcHAb18-DM1 exerted antiproliferative activity in vitro. Antigen-antibody binding and target cells with high growth rate were two integral prerequisites for exerting anti-tumor activity of HcHAb18-DM1. Therefore, we suggest HcHAb18-DM1 is a promising CD147-targeted therapeutic for NSCLC.

CD147 is a tumor-associated antigen that plays a key regulatory role in tumor invasion and distant metastasis. However, the exact role of CD147 phosphorylation, which is deregulated during cancer progression, is unknown. Here, the effects of CD147 phosphorylation on the malignant behavior of hepatocellular carcinoma (HCC) cells and its possible underlying mechanisms are explored. An in situ Duolink-proximity ligation assay (PLA) was used to detect CD147 phosphorylation. Tandem mass spectrometry was employed to identify the phosphorylation sites of CD147. The effects of CD147 phosphorylation on the malignant behavior of HCC cells were evaluated using scratch wound healing assays, transwell invasion assays and cell cycle assays. The genes regulated by CD147 phosphorylation were detected by RNA sequencing. We identified phosphorylated serine-246 in the C terminus of CD147 in primary HCC tissues, whereas serine to alanine substitution mutation analysis suggested that CD147 is phosphorylated mainly at serine-252 in HCC-derived Huh-7 cells. Recovery expression of S246A/S252A mutants in CD147 knockout cells revealed significantly increased migration and invasion capacities compared to wildtype CD147 expressing cells. Cyclophilin A (CyPA) treatment decreased the phosphorylation level of CD147, whereas NIMA-related kinase 6 (NEK6) increased the CD147 phosphorylation level. Moreover, the CD147 phosphorylation level was found to be dramatically decreased in HCC tissues in patients with distant metastases, and a low phosphorylation level of CD147 was found to be associated with a high serum AFP level, recurrence and a poor overall survival. From our data we conclude that hypo-phosphorylated CD147 promotes the migration and invasion of HCC cells and correlates with an unfavorable prognosis in HCC patients, indicating that targeting the aberrantly hypo-phosphorylated form of CD147 may be instrumental for the development of novel therapeutic modalities directed against HCC metastasis.

Milk fat globule-EGF factor 8 (MFGE8) has been reported to play various roles in acute injury and inflammation response. However, the role of MFGE8 in liver injury is poorly investigated. The present research was designed to clarify the expression and function of MFGE8 in carbon tetrachloride (CCl4 )-induced liver injury. Using serum cytokine arrays, we selected a promising cytokine MFGE8 as the candidate in the process of hepatitis-fibrosis-hepatocellular carcinoma (HCC) progression, based on the elevated expression in both hepatic fibrosis and HCC models. We validated the increased expression of MFGE8 in liver tissues and serum samples of acute and chronic CCl4 -induced mice. Immunohistochemistry staining of mouse liver tissues indicated that elevated MFGE8 expression was mainly derived from the injured hepatocytes. In addition, MFGE8 expression in the supernatant of primary hepatocytes was accumulated with prolongation of culture time, and CCl4 treatment further increased the expression of MFGE8. Moreover, a strong correlation between serum MFGE8 expression and liver transaminase activities suggested that MFGE8 may be a novel candidate in liver injury. Intriguingly, mice pretreated with MFGE8 were protected from CCl4 -induced liver injury through antiapoptosis role in the early stage and proproliferation role in the late stage. MFGE8 reduced apoptosis by inhibiting the activation of IRE1α/ASK1/JNK pathway and promoted proliferation by phosphorylation of ERK and AKT. Moreover, serum MFGE8 expression was increased in hepatitis patients while decreased in liver cirrhosis patients. All the results suggest MFGE8 as a novel marker and promising therapeutic agent of liver injury.

Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.

Though the great success of paclitaxel, the variable response of patients to the drug limits its clinical utility and the precise mechanisms underlying the variable response to paclitaxel remain largely unknown. This study aims to verify the role and the underlying mechanisms of CD147 in paclitaxel resistance. Immunostaining was used to analyze human non-small-cell lung cancer (NSCLC) and ovarian cancer tissues. RNA-sequencing was used to identify downstream effectors. Annexin V-FITC/propidium iodide and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect apoptosis. Co-immunoprecipitation (Co-IP), fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were performed to determine protein interactions. Fluorescence recovery after photobleaching (FRAP) was performed to measure the speed of microtubule turnover. Xenograft tumor model was established to evaluate sensitivity of cancer cells to paclitaxel in vivo. In vitro and in vivo assays showed that silencing CD147 sensitized the cancer cells to paclitaxel treatment. CD147 protected cancer cells from paclitaxel-induced caspase-3 mediated apoptosis regardless of p53 status. Truncation analysis showed that the intracellular domain of CD147 (CD147ICD) was indispensable for CD147-regulated sensitivity to paclitaxel. Via screening the interacting proteins of CD147ICD, Ran binding protein 1 (RanBP1) was identified to interact with CD147ICD via its C-terminal tail. Furthermore, we showed that RanBP1 mediated CD147-regulated microtubule stability and dynamics as well as response to paclitaxel treatment. These results demonstrated that CD147 regulated paclitaxel response by interacting with the C-terminal tail of RanBP1 and targeting CD147 may be a promising strategy for preventing paclitaxel resistant.

While immunotherapy has achieved unprecedented success in conquering cancer, the majority of patients develop primary or acquired resistance to immunotherapy, largely in part due to the complicated metabolic networks in the tumor microenvironment. The microenvironmental metabolic networks are woven by a set of metabolic checkpoints, and accumulating evidence indicates that these metabolic checkpoints orchestrate antitumor immunity and immunotherapy. Metabolic checkpoints can regulate T cell development, differentiation and function, orchestrate metabolic competition between tumor cells and infiltrating T cells, and respond to the metabolic stress imposed on the infiltrating T cells. Furthermore, metabolic checkpoints and pathways can modulate the expression profiles of immune checkpoint receptors and ligands and vice versa. Therefore, repurposing interventions targeting metabolic checkpoints might synergize with immunotherapy, and promising approaches to reprogram the metabolic environment are much more warranted. In this review, we summarize recent researches on the metabolic checkpoints and discuss how these metabolic checkpoints regulate antitumor immunity and the promising approaches to modulate these metabolic checkpoints in the combination therapy. A comprehensive and objective understanding of the metabolic checkpoints might help the research and development of novel approaches to antitumor immunotherapy.

SARS-CoV-2 and its variants are raging worldwide. Unfortunately, the global vaccination is not efficient enough to attain a vaccine-based herd-immunity and yet no special and effective drug is developed to contain the spread of the disease. Previously we have identified CD147 as a novel receptor for SARS-CoV-2 infection. Here, we demonstrated that CD147 antibody effectively inhibits infection and cytokine storm caused by SARS-CoV-2 variants. In CD147KO VeroE6 cells, infections of SARS-CoV-2, its variants (B.1.1.7, B.1.351) and pseudovirus mutants (B.1.1.7, B.1.351, B.1.525, B.1.526 (S477N), B.1.526 (E484K), P.1, P.2, B.1.617.1, B.1.617.2) were decreased. Meanwhile, CD147 antibody effectively blocked the entry of variants and pseudomutants in VeroE6 cells, and inhibited the expression of cytokines. A model of SARS-CoV-2-infected hCD147 transgenic mice was constructed, which recapitulated the features of exudative diffuse alveolar damage and dynamic immune responses of COVID-19. CD147 antibody could effectively clear the virus and alveolar exudation, resolving the pneumonia. We found the elevated level of cyclophilin A (CyPA) in plasma of severe/critical cases, and identified CyPA as the most important proinflammatory intermediate causing cytokine storm. Mechanistically, spike protein of SARS-CoV-2 bound to CD147 and initiated the JAK-STAT pathway, which induced expression of CyPA. CyPA reciprocally bound to CD147, triggered MAPK pathway and consequently mediated the expression of cytokine and chemokine. In conclusion, CD147 is a critical target for SARS-CoV-2 variants and CD147 antibody is a promising drug to control the new wave of COVID-19 epidemic.

This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of

Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.

BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147-overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths. Previous studies have suggested that mu-opioid receptor (MOR), a member of the opioid receptor family, is involved in the pathogenesis of HCC. However, the mechanism by which MOR regulates the biological behavior of HCC is still poorly understood. To address this problem, in this study, we investigated the role of MOR in the proliferation of HCC cell lines and the underlying mechanism. First, RT-PCR, western-blot and immunohistochemistry revealed higher expression of MOR in HCC cells and tissue than in non-tumor cells or adjacent tissue, and elevated expression of MOR was associated with jeopardized survival of HCC patients, as demonstrated by bioinformatic databases. Knockdown of MOR by specific siRNA attenuated the proliferation and migration of HCC cells and this effect could be reversed by rescue experiments, confirming the essential role of MOR in the proliferation of HCC. Moreover, results of colony formation assay, CCK8 test, flow cytometry and western blot suggested that a monoclonal antibody (mAb) specifically against MOR could inhibit proliferation of HepG2 and Huh7 cells via the MOR-CD147-p53-MAPK pathway, and the interaction between MOR and CD147 was verified by immunofluorescence colocalization and co-IP analysis. The mAb against MOR also enhanced the cisplatin-induced apoptosis of HCC cells by downregulating p-ERK, Bcl-2 and upregulating Bax. Taken together, these results suggest that MOR could regulate the proliferation of HCC cells in a CD147-p53-MAPK dependent manner. MOR possesses the potential to be a therapeutic target to treat HCC.

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

Cancer has no borders: Generation and analysis of molecular data across multiple centers worldwide is necessary to gain statistically significant clinical insights for the benefit of patients. Here we conceived and standardized a proteotype data generation and analysis workflow enabling distributed data generation and evaluated the quantitative data generated across laboratories of the international Cancer Moonshot consortium. Using harmonized mass spectrometry (MS) instrument platforms and standardized data acquisition procedures, we demonstrate robust, sensitive, and reproducible data generation across eleven international sites on seven consecutive days in a 24/7 operation mode. The data presented from the high-resolution MS1-based quantitative data-independent acquisition (HRMS1-DIA) workflow shows that coordinated proteotype data acquisition is feasible from clinical specimens using such standardized strategies. This work paves the way for the distributed multi-omic digitization of large clinical specimen cohorts across multiple sites as a prerequisite for turning molecular precision medicine into reality., Distributed multi-omic digitization of clinical specimen across multiple sites is a prerequisite for turning molecular precision medicine into reality. Here, the authors show that coordinated proteotype data acquisition is feasible using standardized MS data acquisition and analysis strategies.

Cluster of differentiation 147 (CD147) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD147 overexpression has been reported to facilitate the development of hepatocellular carcinoma (HCC) and influence immunologic disorders. Although increased expression of CD147 was reported in non-alcoholic steatohepatitis (NASH), functions of CD147 in NASH have not been evaluated. Firstly, we confirmed that CD147 expression was increased in the liver tissues from methionine-choline-deficient (MCD) diet-induced NASH model mice and NASH patients. Mice with hepatocyte-specific CD147 deletion exhibited attenuated NASH phenotypes, including reduced steatosis, liver injury, hepatocyte apoptosis and inflammatory cytokines IL-1β/IL-18 secretion. Following the administration of the MCD diet, NLRP3 expression was increased gradually along with CD147 expression. Furthermore, CD147 deletion inhibited the NF-κB/NLRP3 signaling pathway in both MCD diet-induced mice and primary hepatocytes. Finally, CypA inhibitor TMN355 attenuated liver steatosis and injury and inhibited NF-κB/NLRP3 signaling pathway. Therefore, our results suggest that CD147 played a vital role in NASH pathogenesis by regulating the inflammatory response, and CypA/CD147 could be attractive therapeutic targets for NASH treatment.