Xiang-Min Yang

CD147 (Basigin/EMMPRIN), a multifunctional member of the immunoglobulin superfamily (IgSF), is a critical regulator of tumor progression, immune modulation, and metabolic adaptation. Under physiological conditions, it acts as a dynamic scaffold, interacting with monocarboxylate transporters (MCTs), integrins, and cyclophilin A (CyPA) to orchestrate spermatogenesis, embryo implantation, and neural network function. Pathological overexpression of CD147 induces the secretion of matrix metalloproteinases (MMPs), epithelial‐mesenchymal transition (EMT), metabolic reprogramming, and immune evasion, functioning as an independent prognostic biomarker in multiple malignancies. Beyond oncology, CD147 is exploited as an entry receptor for pathogens, including SARS‑CoV‑2, HIV‑1, Plasmodium falciparum , and contributes mechanistically to cardiovascular, autoimmune, and neurodegenerative diseases. Notably, CD147 acts as a fundamental “Energy‐Structure Coupler,” coordinating metabolic flux (via MCTs) with morphogenetic plasticity (via integrins/MMPs) to maintain cellular homeostasis. This review summarizes current insights into CD147's molecular structure, isoforms, post‐translational modifications, and signaling pathways, highlighting its pivotal roles across cancer, infection, autoimmunity, and cardiovascular disease. Finally, we discuss challenges such as the “specificity paradox” and propose emerging strategies to exploit CD147 as a precision biomarker and therapeutic target across diverse diseases.

Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.

The presence of liver cancer stem cells (LCSCs) is one of the reasons for the treatment failure of hepatocellular carcinoma (HCC). For LCSCs, one of their prominent features is metabolism plasticity, which depends on transporters and ion channels to exchange metabolites and ions. The K⁺ channel protein KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) has been reported to promote cell metabolism and malignant progression of HCCs, but its influence on LCSC stemness has remained unclear. Here, we demonstrated that KCNN4 was highly expressed in L-CSCs by RT-PCR and Western blot. Then, we illustrated that KCNN4 promoted the stemness of HC-C cells by CD133⁺CD44⁺ LCSC subpopulation ratio analysis, in vitro stemness transcription factor detection, and sphere formation assay, as well as in vivo orthotopic liver tumor formation and limiting dilution tumorigenesis assays. We also showed that KCNN4 enhanced the glucose metabolism in LCSCs by metabolic enzyme detections and seahorse analysis, and the KCNN4-promoted increase in LCSC ratios was abolished by glycolysis inhibitor 2-DG or OXPHOS inhibitor oligomycin. Collectively, our results suggested that KCNN4 promoted LCSC stemness via enhancing glucose metabolism, and that KCNN4 would be a potential molecular target for eliminating LCSCs in HCC.

Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.

Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il‐6r knock‐in mice and a defined epitope murine anti‐human membrane‐bound IL‐6R (mIL‐6R) mAb named h‐mIL‐6R mAb. We found that the h‐mIL‐6R and the commercial IL‐6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF‐α, IL‐6, IL‐1β, IFN‐γ, transaminases and blood urea nitrogen of LPS‐induced SIRS mice. Besides, the h‐mIL‐6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS‐treated THP‐1 cells in vitro. RNA‐seq analysis indicated that the h‐mIL‐6R mAb could regulate LPS‐induced activation of NF‐κB/Ccl2 and NOD‐like receptor signaling pathways. Furthermore, we found that the h‐mIL‐6R mAb could forwardly inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing NF‐κB in combination with the NF‐κB inhibitor. Collectively, mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation. IL‐6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over‐activated inflammatory responses and alleviating organ injuries in SIRS.

Recently, immunotherapy targeting tumor-infiltrating lymphocytes (TILs) has emerged as a critical and promising treatment in several types of cancer. However, not all cancer types have been tested in immunotherapeutic trials, and different patients and cancer types may have unpredictable clinical outcomes. This situation has created a particular exigency for analyzing the prognostic significance of tumor-infiltrating T cells (TIL-T) and B cells (TIL-B) across different cancer types. To address the critical role of TILs, the abundances of TIL-T and TIL-B cells, as determined by the protein levels of LCK and CD20, were analyzed across heterogeneous human malignancies. TIL-T and TIL-B cells showed varying prognostic significances across heterogeneous cancer types. Additionally, distinct distributions of TIL-T and TIL-B cells were observed in different cancer and tumor microenvironment (TME) subtypes. Next, we analyzed the cellular context for the TME communication network involving the well-acknowledgeable chemokine receptors of TIL-T and TIL-B cells, implying the functional interactions with TME. Additionally, these chemokine receptors, expressed by TIL-T and TIL-B cells, were remarkably correlated with the levels of TIL-T or TIL-B cell infiltrations across nearly all the cancer types, indicating these chemokine receptors as universal targets for up- and down-regulating the TIL-T and TIL-B cells. Lastly, we provide the prognostic landscape of TIL-T and TIL-B cells across 30 cancer types and the subgroups defined by gender, histopathology, histological grade, therapeutic approach, drug, and TME subtype, which are intended to be a resource to fuel the investigations of TILs, with important implications for cancer immunotherapy.

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.

Summary: Background: SARS-CoV-2 is a novel human coronavirus, there is no specific antiviral drugs. It has been proved that host-cell-expressed CD147 could bind spike protein of SARS-CoV-2 and involve in host cell invasion. Antibody against CD147 could block the infection of SARS-CoV-2. We aimed to assess the efficacy and safety of meplazumab, a humanized anti-CD147 antibody, as add-on therapy in patients with COVID-19 pneumonia. Methods: All patients received recommended strategy from Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatments released by National Health Commission of China. Eligible patients were add-on administered 10 mg meplazumab intravenously at days 1, 2, and 5. Patients hospitalized in the same period were observed as concurrent control. The endpoints include virological clearance rate, case severity, chest radiographic, and laboratory test. This trial was approved by the Ethics Committee of Institution at the Tangdu hospital, and registered with ClinicalTrials.gov, NCT 04275245. Findings: 17 patients were enrolled and assigned to meplazumab group between Feb 3, 2020 and Feb 10, 2020. 11 hospitalized patients served as concurrent control. Baseline characteristics were generally balanced across two groups. Compared to control group, meplazumab treatment significantly improved the discharged (p=0.005) and case severity (p=0.021) in patients. The time to virus negative in meplazumab group was reduced than that in control group (median 3, 95%CI[1.5-4.5] vs. 13, [6.5-19.5]; p=0.045, HR=0.374, 95%CI[0.143-0.978]). The percentages of patients recovered to the normal lymphocyte count and CRP concentration were also increased remarkably and rapidly in meplazumab group. No adverse effect was found in meplazumab-treated patients. Interpretation: Meplazumab efficiently improved the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile. Our results support to carry out a large-scale investigation of meplazumab as a treatment for COVID-19 pneumonia. Funding: National Science and Technology Major Project.

Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3′ UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA.