Despite major advances in antiretroviral therapy (ART), a definitive cure for human immunodeficiency virus (HIV) remains elusive. This review aims to propose a unified, multidimensional framework for HIV cure that integrates virologic, immunologic, and clinical perspectives to guide future research and therapeutic strategies. A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant literature on HIV cure research. Articles published primarily between 2008 and 2026 were screened based on relevance, scientific rigor, and contribution to key themes. Findings were synthesized qualitatively to provide an integrated overview of emerging concepts, persistent challenges, and future directions in HIV cure research. Effective HIV cure strategies must integrate three interconnected dimensions: (1) virologic cure through durable suppression or elimination of replication-competent virus, (2) clinical cure through sustained remission without antiretroviral therapy (ART), and (3) immunologic cure through restoration of functional immune competence and inflammatory homeostasis. Current and emerging approaches, including latency-targeting agents, broadly neutralizing antibodies, therapeutic vaccines, immune modulators, and gene-editing technologies, demonstrate potential to bridge viral suppression with immune-mediated control. However, critical challenges persist, including reservoir heterogeneity, immune senescence, viral diversity, and the absence of standardized immunologic metrics. Proposed endpoints extend beyond CD4+ T cell counts to functional T cell responses, immune memory restoration, and normalization of inflammatory profiles. An effective HIV cure must integrate viral suppression, immune restoration, and functional remission. This unified, multidimensional framework provides a foundation for next-generation therapeutic strategies and clinical trial design aimed at achieving durable, host-mediated control.
B lymphocytes, which originally develop in the bone marrow, are key components of humoral immunity and are responsible for antibody production. B lymphocytes arise from progenitor B cells (pro-B cells), which are located in the fetal liver during early development and are generated predominantly in the bone marrow before birth. Based on their stage of maturation and function, B cells are divided into many subsets. B cells play a critical role in the humoral immune response through antibody secretion; however, accumulating evidence indicates that B cells also have more diverse functions in the immune system. Different B cell subsets can modulate effector T-cell responses through antigen presentation, costimulation, and cytokine production. A distinct subpopulation of B cells, termed regulatory B cells (Bregs), negatively regulates cellular immune responses and contributes to the control of inflammation, infectious diseases, autoimmunity, and cancer. These cells may represent viable targets for therapeutic manipulation or immunomodulation independent of antibody production. In this review, we discuss the various B cell subsets and describe non-humoral functions of B cells, with particular emphasis on regulatory B cells and their roles in immunological diseases and cancer.
Chronic hepatitis B (CHB) infection leads to progressive dysfunction and exhaustion of antiviral immune cells, which is a primary obstacle to clinical cure. Although the phenotypic hallmarks of exhausted T cells are well described, the hierarchical trajectory, subset-specific heterogeneity, and underlying mechanisms of exhaustion across the full spectrum of immune cells in the unique hepatic microenvironment remain poorly defined. This review provides a comprehensive and critical synthesis of recent advances in immune exhaustion during CHB. We delineate the common and distinct exhaustion programs among T, B, and natural killer cells, highlighting the pivotal roles of transcription factors and metabolic dysregulation. Furthermore, we critically evaluate the limitations of current evidence and pinpoint critical knowledge gaps, such as the heterogeneity of non-classical exhausted subsets and the liver-resident immune compartment. By framing these findings within a critical and comparative context, this review not only updates our understanding of immune exhaustion but also proposes a roadmap for developing more precise immunotherapies aimed at achieving a functional cure for CHB.
Gallbladder cancer (GBC) is a prevalent and aggressive malignancy of the biliary system. Studies have revealed that Proteasome 26S subunit ATPase 2 (PSMC2) is overexpressed and associated with the development process of several cancers. However, the specific role in GBC remains unknown. This study aims to explore the association between PSMC2 and GBC pathogenesis. We assessed PSMC2 expression from normal and GBC patient samples. Using Cell Counting Kit-8 (CCK-8), colony formation, scratch, and Transwell migration assays, we investigated the effects of PSMC2 on the proliferation and migration of GBC cells. Subsequently, through bioinformatics analysis, we identified the cell cycle pathways related to PSMC2 in GBC cells. Using flow cytometry, we identified that knocking down PSMC2 could alter the cell cycle in GBC cells. Then, through bioinformatics analysis and Western blot assay, we discovered the relationship between the AKT/Cyclin D1/CDK6 pathway and the cell cycle and used an RAC-alpha serine/threonine-protein kinase (AKT) inhibitor and an Cyclin-Dependent Kinase 6 (CDK6) inhibitor to restore the GBC cell proliferation induced by PSMC2 overexpression in order to detect the mechanism of PSMC2's role in GBC. We found that PSMC2 was observably upregulated in GBC patient samples. In vitro experiments demonstrated that knocking down PSMC2 significantly suppressed the GBC cells' proliferation and migration abilities. Bioinformatics assays showed a significant enrichment of the cell cycle pathway in both the GO and KEGG databases. Furthermore, cell cycle-related genes CDK6 and Cyclin D1 were significantly upregulated in PSMC2-high expressed clusters. Then we identified that knockdown of PSMC2 could suppress AKT activation and reduce the expression of Cyclin D1 and CDK6. Moreover, treatment with the AKT inhibitor could restore the upregulated CDK6 expression after PSMC2 overexpression, and treatment with the CDK6 inhibitor restored the progression and altered the cell cycle distribution in GBC cells induced by PSMC2 overexpression. PSMC2 was significantly upregulated in GBC tissues and cell lines. PSMC2 expression promotes progression and migration in GBC cells, potentially through regulation of the AKT/Cyclin D1/CDK6 signaling pathway.
The aim of this study is to identify and validate ketogenesis-immune cross-talk genes with prognostic significance in LUAD patients. Bulk RNA-seq data of LUAD were obtained from TCGA and GEO databases to analyze differentially expressed genes (DEGs), which were intersected with ketogenesis-related gene sets from MSigDB. DEGs associated with anti-PD-1 therapy sensitivity were further identified. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic genes. Molecular subtypes and an 8-gene ketogenesis-immune prognostic signature were constructed and validated. Single-cell RNA-seq data were used to map cell-type-specific expression of prognostic genes. Functional effects of SLC2A1, a key metabolic regulator, were evaluated in A549 cells using overexpression/knockdown approaches combined with β-hydroxybutyrate (BHB) treatment. A total of 135 ketogenesis-immune cross-talk genes were identified. Consensus clustering defined two LUAD subtypes with distinct prognosis and immune landscapes. Single-cell analysis revealed SLC2A1 enrichment in epithelial tumor cells. Functional assays showed that SLC2A1 overexpression enhanced proliferation, migration, glycolysis, and ATP production, whereas knockdown suppressed these processes; BHB partially rescued energy deficits in SLC2A1-deficient cells. Mechanistically, SLC2A1 regulated ketone-body utilization and AMPK/mTOR signaling, linking metabolic reprogramming with tumor growth and immune modulation. SLC2A1 is a critical regulator of ketone-body metabolism in LUAD and serves as a potential prognostic factor.
Type I interferons (IFN-I) exert a significant influence on the immune system. Produced by certain immune cells, they affect other immune cells and mediate diverse effects, including antiviral activity, inhibition of tumor growth, and suppression of cell proliferation. IFN-I is also implicated in the development and persistence of autoimmune disorders. Research has shown that abnormal IFN-I levels and IFN-I-regulated gene expression in the blood or tissues of individuals with autoimmune diseases are associated with disease onset, clinical manifestations, and severity. Monogenic conditions known as Type I interferonopathies-caused by mutations affecting the IFN-I signaling pathway-share clinical features with systemic lupus erythematosus (SLE). Both preclinical models and clinical trials targeting the IFN-I signaling pathway have yielded promising results for the treatment of autoimmune diseases. This review provides an overview of the interplay between epigenetics, various types of RNAs, transcription factors, and IFN-I. It discusses epigenetic modifications and transcription factor dysregulation, offering insights into disease mechanisms and potential future therapeutic advancements.
Phosphatidylinositol 4-kinase beta (PI4Kβ) is an essential lipid kinase in Plasmodium species, central to intracellular signaling, vesicular trafficking, and parasite development. Recent insights suggest PI4Kβ also plays a key role in modulating host immune responses. Through regulation of protein export, immune evasion mechanisms, and extracellular vesicle formation, PI4Kβ influences the immune landscape during malaria infection. Notably, inhibition of PI4Kβ disrupts parasite survival and may enhance immune recognition by impairing virulence factor trafficking and improving antigen presentation. Targeting PI4Kβ offers a promising dual-action strategy-direct antiplasmodial effects coupled with immunomodulation. This review explores PI4Kβ's emerging role at the interface of parasite survival and host immunity, highlighting its therapeutic potential as both an antiparasitic and immunomodulatory target. Further investigation is warranted to evaluate its role in antigen processing, vaccine responsiveness, and combinatorial immunotherapy. PI4Kβ stands out as a next-generation target for integrated malaria intervention strategies.
Oral squamous cell carcinoma (OSCC) begins with pre-existing oral potential malignant diseases (OP-MDs), among which oral leukoplakia (OL) is the most common precancerous lesion. This study systematically explored the mechanism of N6-methyladenosine (m6A) RNA methylation in the occurrence and development of OSCC by integrating bioinformatics analysis and experimental verification. Based on the analysis of the GSE85195 dataset, we identified the key differentially expressed genes (DEGs) and m6A regulatory factors in the progression from OL to OSCC. Functional enrichment analysis revealed that these genes were significantly enriched in the extracellular matrix (ECM) signaling pathway. By constructing a protein-protein interaction network, we identified THBS1 as the core hub gene, and survival analysis revealed that the high expression of THBS1 was associated with a poor prognosis of OSCC patients. Bioinformatics analysis found that IGF2BP2 could regulate the expression of THBS1 through m6A. In vitro assays indicated that IGF2BP2 can regulate the expression of THBS1, and knockdown of IGF2BP2 can significantly inhibit the proliferation, migration, and invasion abilities of OSCC cells. Further analysis revealed that the risk score based on IGF2BP2, THBS1, and tumor stage was closely associated with tumor immune microenvironment characteristics. These evidences not only reveal a potential new mechanism by which m6A modification may mediate the IGF2BP2-THBS1 axis to promote the progression of OSCC, but also provide a new theoretical basis for understanding the remodeling of the immune microenvironment of OSCC.
Background: Non-small cell lung cancer (NSCLC) is a type of lung cancer with high mortality. Mesenchymal-to-epithelial transition (MET) fusions are present in NSCLC and are associated with tumorigenesis. The Ephrin type-B receptor 4 (EPHB4)-MET fusion gene is a recently discovered gene, and there is a lack of research on its oncogenicity and driving mechanisms. In this study, we focused on the oncogenic properties and mechanism of the EPHB4-MET fusion gene. Methods: To create EPHB4-MET gene fusion cells, BEAS-2B cells were infected with lentivirus harboring EPHB4-MET. The expression efficiency was measured using reverse-transcriptase polymerase chain reaction (RT-PCR). Subsequently, cell counting kit-8 (CCK-8), crystal violet staining, and transwell assays were performed to investigate the oncogenicity of EPHB4-MET gene fusion. Finally, dual luciferase assay and chromatin immunoprecipitation (ChIP) were used to probe the binding of homeobox domain transcription factor A9 (HOXA9) to the EPHB4 promoter. Results: EPHB4-MET expression increased after infection with lentivirus, indicating that the gene fusion cell construction was successful. In addition, EPHB4-MET promoted MET activation of the downstream AKT pathway. Genes harboring EPHB4-MET significantly promoted cell proliferation, cell migration, and invasion. Subsequent research showed that via binding to the EPHB4 promoter region, HOXA9 induced the expression of EPHB4-MET, and knockdown of HOXA9 inhibited EPHB4-MET-induced oncogenic properties. Conclusion: In this study, we demonstrated that HOXA9 drove the expression of the fusion gene EPHB4-MET and exerted a tumorigenesis signature. HOXA9 may be a useful target for both diagnosis and treatment in patients with EPHB4-MET fusion genes in lung cancer.
Background: The substantial infiltration of M2 macrophages in ovarian cancer (OC) signifies a poor prognosis, although the precise mechanisms remain unclear. The pivotal role played by Secreted phosphoprotein 1 (SP-P1)-regulated macrophage polarization is evident. This study seeks to validate the role of SPP1 and macrophages within the OC tumor microenvironment (TME), potentially laying the groundwork for therapeutic approaches in ovarian cancer. Methods: Using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we analyzed the immune infiltration characteristics in OC and unearthed the functions of macrophages. Additionally, we conducted immunohistochemistry (IHC) analysis to assess the expression of SPP1 and CD206 in OC tissues patients. Furthermore, we utilized flow cytometry to analyze the infiltration and polarization of CD206-positive cells. Subsequently, we employed ELISA to investigate SPP1 secretion and Western blot analysis to assess ARG1 protein expression. Next, transwell assays were utilized to evaluate the invasive capabilities of macrophages following SPP1 intervention. Finally, EDU assays were performed to analyze the proliferative capacity of OC cells. Results: We discovered that the infiltration of SPP1+ macrophages was a distinctive feature of OC TME. Our findings confirmed the high expression of CD206 in OC, along with abundant SPP1 expression in tissues exhibiting high CD206 levels. Furthermore, this association correlated closely with worse tumor staging, ascites, HRD mutations, and peritoneal metastasis, suggesting a poor prognosis associated with SPP1+CD206 infiltration. Additionally, we observed that lactate regulates the secretion of SPP1. Moreover, SPP1-high macrophages could promote the proliferation of ovarian cancer cells. Conclusion: Our study identified the role of SPP1+macrophage in OC which may accelerated the metastasis and proliferation of OC.
BACKGROUND:Ursolic acid (UA) and Rosuvastatin (RST) improves diabetic nephropathy (DN). However, the combination therapy of UA and RST on DN and its possible mechanism requires exploration. METHODS:Streptozotocin (STZ)-induced DN model cells were treated with UA and RST alone or in combination. Cell viability and apoptosis were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry, and TUNEL staining. The inflammation-related factors' release was examined by enzyme linked immunosorbent assay (ELISA). Potential mechanism was analyzed through network pharmacology. The reactive oxygen species (ROS) accumulation was detected using flow cytometry. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and catalase (CAT) were measured using commercial reagent kits. RESULTS:UA and RST increased viability while reducing apoptosis of STZ-induced cells. UA and RST suppressed the release of inflammation-related factors in STZ-induced cells. Through network pharmacology analysis, the inflammation and oxidative stress were thought to be implicated in the treatment of UA and RST in DN. UA and RST downregulated ROS and MDA while upregulating SOD and CAT in STZ-induced cells. Compared with RST and UA used individually, their combination showed a more potent effect in increasing viability, mitigating apoptosis, and suppressing the inflammation and oxidative stress in STZ-induced cells. CONCLUSION:Combined UA and RST therapy ameliorated the inflammation and oxidative stress in DN model cells, providing the theoretical basis for pharmacological research of DN.
BACKGROUND:Membranous nephropathy (MN) is an autoimmune kidney disease, and its pathogenesis is related to inflammation and podocyte injury. Both disulfiram and baicalin can relieve the symptoms of MN through anti-inflammatory effects. However, it is still unclear whether disulfiram and baicalin can enhance the therapeutic effect of MN by combination therapy. METHODS:We screened the optimal drug concentration of disulfiram and baicalin for incubation of AB8/13 cells by CCK-8 assay. Angiotensin II was used to stimulate AB8/13 cells to construct a MN cell model. Subsequently, cell proliferation assays, network pharmacology analysis, ELISA assay, and pyroptosis detection were employed to investigate the effects of disulfiram combined with baicalin in MN. RESULTS:Firstly, 250 nM disulfiram and 5 μmol/L baicalin were selected as the optimal dose for the treatment of MN. Cell proliferation assay showed that the combined administration of disulfiram and baicalin could reduce Angiotensin II-induced podocyte injury. Subsequently, a total of 129 genes were identified as potential therapeutic targets of the combination therapy involving disulfiram and baicalin for MN. These targets mainly focused on regulating inflammatory-related functions and pathways. Disulfiram combined with baicalin inhibited the inflammation of MN by suppressing the levels of TNF-α, IL-8 and C-reactive protein and promoting the levels of TGF-β and IL-10. Disulfiram combined with baicalin significantly attenuated Angiotensin II-induced podocyte pyroptosis, as indicated by reduction of Caspase-1 and GSDMD-N, lactate dehydrogenase release and the percentage of podocytes stained with propidium iodide. CONCLUSION:Compared with monotherapy using either disulfiram or baicalin alone for MN, the combination has a protective role in podocyte injury by inhibiting inflammation and pyroptosis. This discovery provides a new perspective for clarifying the pharmacological effects of disulfiram and baicalin to podocyte injury in MN.
OBJECTIVES:Primary Sjögren's syndrome (pSS) is characterized by molecular heterogeneity and immune-metabolic dysregulation. This study aimed to identify diagnostic biomarkers and characterize monocyte-macrophage differentiation trajectories in pSS. METHODS:Bulk RNA-seq data were first batch-corrected and subjected to differential expression analysis, immune infiltration profiling, and weighted gene co-expression network analysis (WGCNA) to identify key gene modules. For single-cell RNA-seq, 42,157 salivary gland cells were clustered and annotated; Monocle3 pseudotime analysis reconstructed the monocyte-macrophage differentiation trajectory, and CellChat quantified intercellular signaling networks. Candidate immune-metabolism biomarkers were then screened by integrating WGCNA results with three machine-learning algorithms, LASSO regression, SVM-RFE, and random forest, and validated in the external GSE84844 cohort. Finally, functional relevance was tested in PMA-induced THP-1 macrophages by knocking down ISG15 and measuring effects on NF-κB activation and secretion of TNF-α and IL-1β. RESULTS:Pseudotime analysis delineated a monocyte-to-macrophage differentiation axis and pinpointed 182 dynamic marker genes. Integrated machine-learning and network analysis highlighted four immune-metabolism genesISG15, OAS1, LAP3, and PARP9each achieving AUC > 0.80 in the GSE84844 validation set. In vitro, ISG15 knockdown markedly attenuated NF-κB activation and reduced TNF-α/IL-1β release, confirming its pivotal role in pSS-associated inflammation. CONCLUSIONS:This integrated transcriptomic analysis highlights key monocyte-macrophage trajectories and identifies four robust immune-metabolism biomarker candidates for pSS diagnosis. Functional validation of ISG15 suggests it plays a pivotal role in driving macrophage-mediated inflammatory responses in pSS.
Cervical squamous cell carcinoma (CSCC) has an unfavorable prognosis with major therapeutic challenges. Natural killer (NK) cells play a pivotal function in anti-tumor immunity. However, the correlation between NK cells and heterogeneity and prognosis in CSCC lacks definitive understanding. This study seeks to elucidate the potential value of high-activity NK cell-related genes in prognosis and immunotherapy for CSCC. Transcriptome and single-cell sequencing data of people with CSCC were obtained from TCGA and EMBL-EBI databases, respectively. Single-cell data underwent quality control, dimensionality reduction, and identification of high-activity NK cells and their marker genes. After WGCNA application to screen NK-related genes. a prognostic risk model was constructed employing univariate Cox, LASSO Cox regression, and multivariate Cox regression analyses. The clinical implication of the model was validated through immune infiltration assessment, survival, gene set enrichment, tumor mutation analyses, and drug sensitivity prediction. High-activity NK cells and associated genes in CSCC were identified. A risk prognostic model based on high-activity NK-related genes was developed, yielding six key prognostic genes (RIPOR2, PTGER4, BIN2, MARCHF2, SPATA13, KLRC2). The model demonstrated robust predictive performance in training and validation sets. Patients in the low-risk group exhibited higher infiltration levels of NK, CD8+T, and dendritic cells, along with increased sensitivity to immune checkpoint inhibitor therapy. Additionally, drug sensitivity analysis identified promising therapeutic candidates. This study, integrating single-cell and RNA sequencing, revealed the heterogeneity of NK cells in CSCC. The risk prognostic model provided prognostic biomarkers and therapeutic targets for CSCC patients, offering a theoretical foundation for immunotherapy research.
Immunogenic cell death (ICD), a recently identified form of cell death capable of stimulating the immune system, holds significant potential for cancer therapy. While long non-coding RNAs (lncRNAs) regulate diverse cellular processes, the role and prognostic value of ICD-related lncRNAs (ICDRLs) in osteosarcoma (OS) remain unclear. This study aimed to establish an ICDRL-based prognostic signature for OS. Utilizing gene expression profiles and clinical data from TARGET and GTEx databases, along with published ICD-related genes (ICDRGs), we identified ICDRLs via co-expression analysis, differential expression screening, univariate Cox regression, and LASSO regression. A novel prognostic signature comprising three ICDRLs (ELFN1-AS1, LINC01094, SATB2-AS1) was constructed. The signature demonstrated significant prognostic predictive power, confirmed by receiver operating characteristic curve analysis, and functioned as an independent prognostic factor. Moreover, the signature reflects the tumor immune microenvironment and predicts distinct chemotherapy responses, guiding OS treatment strategies.
DNA Damage-Inducible Transcript 4 (DDIT4), a conserved stress-responsive protein with dual nuclear and cytoplasmic localization, has recently emerged as a critical regulator in multiple cancer types. However, its functional role and molecular mechanisms in hepatocellular carcinoma (HCC) remain poorly understood. In this study, we systematically investigated DDIT4's biological significance through comprehensive in vitro analyses. Clinical specimen analysis revealed significant downregulation of DDIT4 protein in HCC tumor tissues compared to adjacent non-tumor controls. Functional studies demonstrated that DDIT4 knockdown markedly enhanced HCC cell proliferation, whereas its overexpression exerted potent anti-proliferative effects. Mechanistically, our in vitro experiments revealed two key regulatory pathways: (1) DDIT4 overexpression suppressedAKT/mTOR signaling activation, and (2) DDIT4 underwent ubiquitin-mediated proteasomal degradation via specific interaction with the E3 ligase Seven in Absentia Homologue 2 (SIAH2). These findings establish DDIT4 as a tumor-suppressive protein in HCC pathogenesis, whose oncogenic downregulation is mediated through SIAH2-dependent ubiquitination. The resultant decrease in DDIT4 protein levels creates a permissive microenvironment for tumor growth by releasing AKT/mTOR pathway inhibition. Our results nominate DDIT4 as a promising therapeutic target for HCC intervention. Further preclinical and clinical investigations are warranted to validate DDIT4's translational potential and explore targeted strategies to stabilize its tumor-suppressive functions.
