J Transl Med [JOURNAL]
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200 papers
Gamabufotalin suppresses pancreatic cancer through redox-homeostasis disruption by G6PD downregulation.
Xu D, Wang X, Cai Y … +5 more , Zheng P, Zhu L, Peng W, Song Y, Chen B
J Transl Med · 2026 Jun · PMID 42310762 · Full text
BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths worldwide, highlighting the critical need for novel therapeutic strategies. Gamabufotalin (CS-6), a bufadienolide compound, has been shown to exer...
BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths worldwide, highlighting the critical need for novel therapeutic strategies. Gamabufotalin (CS-6), a bufadienolide compound, has been shown to exert significant inhibitory effects on a variety of cancers. OBJECTIVE: This study investigates the potential therapeutic effects and underlying molecular mechanisms of CS-6 in pancreatic cancer. METHODS: The anti-cancer properties of CS-6 were assessed through both in vivo and in vitro experiments. Network pharmacology and untargeted metabolomics were employed to identify candidate molecular targets of CS-6. Molecular docking, molecular dynamics simulations, and CETSA were used to support potential target engagement between CS-6 and G6PD. G6PD expression was evaluated through public databases and immunohistochemistry. NADPH levels, ROS accumulation, apoptosis, and autophagy were measured using NADPH assays, western blot, flow cytometry, and transmission electron microscopy. Transcriptomic analysis and western blot were conducted to explore the downstream signaling pathways affected by G6PD downregulation. RESULTS: CS-6 inhibited pancreatic cancer cell growth, migration, and invasion, while promoting apoptosis. In vivo, CS-6 suppressed tumor growth and induced cell death. Elevated G6PD expression in pancreatic cancer was associated with poor prognosis. CS-6 treatment reduced NADPH levels, increased ROS accumulation, and was associated with autophagy induction, accompanied by decreased G6PD protein expression. Furthermore, CS-6 inhibited the PI3K/AKT signaling pathway, and G6PD knockdown recapitulated this effect. CONCLUSION: CS-6 treatment is associated with G6PD downregulation, redox-homeostasis disruption, and suppression of the PI3K/AKT signaling pathway, thereby contributing to autophagy-related cell death, apoptosis, and inhibition of pancreatic cancer progression. These findings highlight CS-6 as a promising therapeutic candidate for pancreatic cancer treatment, with G6PD as a potential molecular target.
Multiomics prediction and immunogenic validation of personalized neoantigens in cholangiocarcinoma patients.
Zhang B, Jin B, Wan X … +12 more , Liu X, Wu X, Xing J, Wang Y, Xu H, Xu Y, Guan M, Mao Y, Bai Y, Zhu J, Chen Q, Du S
J Transl Med · 2026 Jun · PMID 42310758 · Full text
BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with limited treatment options, underscoring the need for breakthrough precision therapies. Neoantigen-based therapy is a promising novel strateg...
BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with limited treatment options, underscoring the need for breakthrough precision therapies. Neoantigen-based therapy is a promising novel strategy for cancer treatment. This study investigates the potential of neoantigen peptides in CCA, emphasizing their role in personalized immunotherapy and providing insights for vaccine design. METHODS: Paired samples from 33 CCA patients underwent whole-exome sequencing and RNA sequencing to profile the mutational and neoantigen landscape. Besides, personalized neoantigen peptides were synthesized and immunogenicity was validated through enzyme-linked immunospot assay. Meanwhile, corresponding T cell receptor (TCR) sequences were predicted by bioinformatics. RESULTS: TP53 was the most frequently mutated gene (57.58%) and a significant positive correlation between tumor mutational burden and neoantigen load was observed (r = 0.6511, p < 0.0001). A total of 798 neoantigens were identified in 22 samples, predominantly characterized by human leukocyte antigen (HLA) A02:07 and A02:01. Additionally, 16 neoantigen peptides from three CCA patients were successfully synthesized and these peptides induced robust T-cell responses, with the most potent epitopes derived from UBN1, C2orf47 and ITPR2. Moreover, bioinformatic analysis further predicted in silico putative TCR sequences potentially associated with the candidate neoantigens. In Pt01, the Vβ5-6Jβ1-2 sequence had the highest predicted affinity; in Pt02, the Vβ2Jβ1-4 sequence had the highest predicted affinity; and in Pt03, the Vβ29-1Jβ2-7 sequence had the highest predicted affinity. The sequence motifs of the high-frequency TCR clusters were also demonstrated. CONCLUSIONS: Our findings show that candidate immunogenic neoantigen peptides can be identified in CCA and are supported by proof-of-concept functional validation. Together, these results provide a framework for the downstream validation of neoantigen targets and the development of personalized immunotherapy approaches.
Hypoxia/lactate orchestrates the reprogramming metabolism of lung adenocarcinoma by modulating the SIRT2-mediated acetylation.
Tao J, Chen ZY, Xun JN … +6 more , Wang M, Liu JX, Zhang Y, Lowrie DB, Li Y, Fan XY
J Transl Med · 2026 Jun · PMID 42310756 · Full text
BACKGROUND: Silent information regulator 2 (SIRT2) has been described to have dual roles as an oncogene and tumor suppressor gene in non-small cell lung cancer, but its functional selection and the precise mechanisms of...
BACKGROUND: Silent information regulator 2 (SIRT2) has been described to have dual roles as an oncogene and tumor suppressor gene in non-small cell lung cancer, but its functional selection and the precise mechanisms of its action remain to be elucidated. METHODS: lung adenocarcinoma (LUAD) tissue microarrays and cell lines were used to detect SIRT2 expression using Immunohistochemistry and Western blotting. SIRT2 overexpression, knockdown, and knockout LUAD cells were constructed to test SIRT2 function in vitro and in vivo, and targeted metabolomics, proteomics, and acetylation analyses were performed to explore the detailed mechanisms by which SIRT2 affects the biological characteristics of LUAD. RESULTS: SIRT2 is not only downregulated in LUAD tissues and cells, but also associated with poor prognosis in LUAD patients, not in lung squamous cell carcinoma. We also found that hypoxia-induced increasement in lactate levels led to this decreased SIRT2 expression. Remarkably, SIRT2 deficiency promotes the proliferation and metastasis of LUAD cells in vitro and in vivo, while SIRT2 overexpression exerts the opposite function. Mechanistically, SIRT2 deficiency leaded to increased acetylation levels of multiple enzymes involved in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and glutaminolysis. And results of co-inmunoprecipitation showed that SIRT2 bound to the above enzymes. Accordingly, SIRT2-deficient LUAD cells showed altered metabolic activities such as glycolysis, pentose phosphate pathway, TCA cycle, serine metabolism, and urea cycle. Notably, SIRT2 deletion increases glycolytic capacity of LUAD cells by increasing the acetylation modification of LDHA at the K118 site. CONCLUSION: This study reveals that hypoxia-induced lactate elevation decreases SIRT2 expression to promote LUAD progression, with the mechanism related to promoting glycolysis by increasing LDHA acetylation. In addition, decreased SIRT2 expression has also been found to cause alterations in many metabolic pathways with no verification mechanism.
CD45 as a multifunctional target in immune regulation and therapeutic delivery.
Zhao K, Yang R, Li M … +4 more , Zhang Z, Liu J, Shi J, Zhao X
J Transl Med · 2026 Jun · PMID 42310751 · Full text
BACKGROUND: CD45, a receptor-type protein tyrosine phosphatase broadly expressed on leukocytes, is a critical regulator of signaling thresholds and immune cell activation. Dysregulation of CD45 has been implicated in a r...
BACKGROUND: CD45, a receptor-type protein tyrosine phosphatase broadly expressed on leukocytes, is a critical regulator of signaling thresholds and immune cell activation. Dysregulation of CD45 has been implicated in a range of immune-related diseases and malignancies. MAIN BODY: Recent advances have focused on modulating CD45 for disease treatment through various strategies, including regulating its expression level, structural conformation, and spatial membrane distribution. Beyond the immunomodulatory role, as a leukocyte-specific and broadly expressed biomarker, CD45 also has broad application in the field of drug delivery, such as the development of CD45 antibody-drug conjugates and a drug-loading site on live-cell carriers. CONCLUSIONS: This review systematically summarizes the immunoregulatory mechanisms of CD45 across various immune cell subsets and discusses CD45-based therapeutic interventions and drug delivery strategies, bridging basic immunology with therapeutic advancement.
Precise control of switchable chimeric antigen receptor T cells allows enhanced safety and less T cell exhaustion.
Zhang ZA, Herring L, Shwe TH … +4 more , Hu Y, Song X, Cao W, Liu WR
J Transl Med · 2026 Jun · PMID 42310743 · Full text
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in hematologic malignancies, yet their clinical utility remains limited by safety concerns, limited persistence, and T-cell ex...
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in hematologic malignancies, yet their clinical utility remains limited by safety concerns, limited persistence, and T-cell exhaustion driven by continuous receptor signaling. While switchable CAR designs provide external control, many reported systems are irreversible, strictly binary, or compromise CAR-T potency. METHODS: We engineered an optimized chemically switchable CAR platform (CSN CAR) that pharmacologically regulates antigen engagement by controlling the surface expression of the full-length CAR. An NS3 protease module was embedded within the CAR construct to enable drug-dependent stabilization of intact CAR on T cells. Using engineered CAR-T cells, we quantified drug-controlled activation, cytotoxicity, and cytokine release against CD19⁺ tumor cells by flow cytometry and ELISA in vitro. We further screened clinically approved NS3/4A inhibitors in CAR-HEK and CAR-T cells to identify optimal small-molecule controllers. A chronic stimulation model was established to assess CAR-T persistence and exhaustion-associated phenotypes in vitro. RESULTS: CSN CAR-T cells enabled precise, dose-dependent regulation of CAR surface density, cytokine production, and cytotoxicity. In the OFF state, switchable CAR-T cells showed minimal basal activity, consistent with reduced antigen-driven activation and cytokine release in the absence of drug in the experimental conditions. Upon drug addition, intact surface CAR was detectable within 1 h, reaching ~ 80% of peak observed CAR expression by 4 h. Reversible suppression of CAR expression enabled attenuation of cytotoxicity toward normal CD19⁺ B cells in vitro after target-cell reduction, supporting a potential strategy to mitigate prolonged on-target/off-tumor activity. Under chronic stimulation, switchable CAR-T cells exhibited reduced exhaustion-associated markers, more stable CAR expression, and preferential differentiation toward a central memory phenotype. CONCLUSION: Together, these findings establish CSN CAR as a reversible and tunable switchable CAR-T platform enabled by clinically approved NS3/4A inhibitors, supporting controllable modulation of CAR activity with potential applications for improving the precision and safety of CAR-T cell therapy.
PD-1 and TIGIT coexpression enables selective enrichment of clonally expanded tumor-reactive CD8 T cells for melanoma TIL therapy.
Ducoin K, Beauvais T, Goward J … +11 more , Ahondo M, Lambot S, Mordelet A, Daminette A, Thabot M, Deng J, Tian S, Rulli S, Quereux G, Khammari A, Labarrière N
J Transl Med · 2026 Jun · PMID 42310741 · Full text
BACKGROUND: Although anti-PD-1 antibodies are approved as first-line treatment for patients with metastatic melanoma (MM), many patients remain resistant. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes...
BACKGROUND: Although anti-PD-1 antibodies are approved as first-line treatment for patients with metastatic melanoma (MM), many patients remain resistant. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) represents a promising alternative or complementary strategy, but heterogeneous clinical response rates indicate that TIL-ACT still requires optimization, particularly through enrichment of tumor-specific T lymphocytes. We recently identified a circulating CD8⁺ T-cell population, termed DPOS, defined by PD-1 and TIGIT coexpression, whose frequency correlates with anti-PD-1 efficacy in MM patients. Because these activated CD8⁺ T cells are enriched in melanoma antigen-specific lymphocytes, we hypothesized that this biomarker combination could enable the selective isolation of TILs with high therapeutic potential. METHODS: Deep immunophenotyping, T-cell receptor (TCR) sequencing, in vitro functional assays, and in vivo patient-derived xenograft models were used to characterize and evaluate the antitumor reactivity of the DPOS subset. A clinically compatible workflow for selective isolation and expansion of DPOS TILs was developed using flow cytometry sorting and ex vivo expansion. RESULTS: DPOS TILs displayed high expression of activation, costimulatory, tissue residency, and pre-exhaustion markers, consistent with an effector-memory phenotype, while maintaining proliferative capacities similar to other CD8⁺ TILs. TCR sequencing and ELISpot assays demonstrated that the DPOS subset is enriched in clonally expanded tumor antigen-specific T cells, with limited overlap between dominant DPOS clonotypes and those from the remaining CD8⁺ TIL compartment. Co-culture assays against autologous tumor cell lines demonstrated that DPOS TILs mediate stronger tumor recognition, characterized by increased cytotoxicity, cytokine secretion, and proliferation following antigen encounter. These functional advantages translated into improved tumor control in two patient-derived xenograft models. CONCLUSION: PD-1⁺TIGIT⁺ CD8⁺ TILs define a distinct tumor-reactive population within human melanoma lesions. Our findings support the use of PD-1/TIGIT coexpression as a clinically applicable strategy to enrich functionally tumor-reactive CD8⁺ T cells and provide a rationale for biomarker-guided optimization of TIL-based adoptive cell therapy in melanoma.
Serotonin 5-HT7 receptor signaling modulates inflammatory responses and survival after myocardial infarction.
Müller FE, Bahr FS, Erschow S … +14 more , Kasten M, Heimerl M, Benen N, Jung M, Schmidt A, Scherr M, Falk CS, Bustamante C, Ponomarev I, Bauersachs J, Hilfiker-Kleiner D, Thum T, Ponimaskin EG, Ricke-Hoch M
J Transl Med · 2026 Jun · PMID 42310735 · Full text
BACKGROUND: Myocardial infarction (MI) is among the leading causes of death worldwide, and a precisely regulated inflammatory response is essential for effective cardiac repair and long-term outcome. The serotonergic sys...
BACKGROUND: Myocardial infarction (MI) is among the leading causes of death worldwide, and a precisely regulated inflammatory response is essential for effective cardiac repair and long-term outcome. The serotonergic system regulates immune cell functions, yet its contribution to post-MI remodeling is incompletely understood. METHODS: Here, we investigated the role of serotonin receptor 7 (5-HT7R) in post-infarction inflammation and outcome after permanent left anterior coronary artery ligation in mice, and complementary analysis of peripheral blood mononuclear cells (PBMCs) obtained from patients with acute MI. RESULTS: Three days after MI, 5-HT7R mRNA expression was significantly upregulated in the infarct region compared to remote myocardium and sham operated mice. RNA-sequencing of isolated murine CD11b cells demonstrated high 5-HT7R expression in cardiac macrophages during the acute phase, which was confirmed by immunohistochemistry. Systemic 5-HT7R-knockout did not affect basal cardiac function but resulted in impaired left ventricular function and enhanced inflammatory signatures 14 days after MI without changes in infarct size. Pharmacological activation of 5-HT7R signaling with the selective agonist LP-211 increased survival after MI, although global systolic function among survivors was not improved. Transcriptomic profiling of cardiac macrophages 3 days after MI revealed bidirectional regulation of inflammatory and metabolic programs depending on 5-HT7R activity, including altered expression of Got1 and S100A9. Complementary, in PBMCs from MI patients Got1 expression was reduced, while S100A9 was increased, and both correlated with 5-HT7R expression. CONCLUSIONS: These data suggest 5-HT7R as a regulator of post-MI immune responses and a potential target to improve repair and survival.
SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.
Wang S, Zhao X, Dong J … +8 more , Zhang J, Wang Y, Jin H, Jiang X, Chen L, Zhang M, Ji L, Zhao Y
J Transl Med · 2026 Jun · PMID 42310679 · Full text
BACKGROUND: Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signaling molecule involved in tumor proliferation, invasion, metastasis, and immune evasion. In gastrointestinal (GI) canc...
BACKGROUND: Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signaling molecule involved in tumor proliferation, invasion, metastasis, and immune evasion. In gastrointestinal (GI) cancers, however, its function is highly complex and context-dependent, varying across distinct cellular compartments within the tumor microenvironment (TME). MAIN BODY: This review focuses on five major GI malignancies and reframes SHP2 function within a GI-specific TME, emphasizing how its roles are shaped by key environmental determinants-including cell type, tissue microenvironment, and disease state. We further discuss how current therapeutic modalities, such as chemotherapy, radiotherapy, and targeted therapy, modulate SHP2 activity and contribute to treatment resistance. In addition, we evaluate the therapeutic potential of SHP2 inhibition, highlighting recent advances in allosteric inhibitors, emerging combination strategies, and ongoing clinical studies. CONCLUSIONS: Together, this review provides a conceptual framework for understanding SHP2 as both a signaling integrator and a precision therapeutic target in GI cancers, offering insights that may inform future mechanistic studies and the development of context-aware therapeutic strategies.
TYRP1 defines a proliferative melanoma cell subpopulation, driving malignant progression and therapy resistance via the GPNMB-Notch1-SOX10/MITF axis.
Hu C, Zhu L, Fan P … +2 more , Bu X, Zuo C
J Transl Med · 2026 Jun · PMID 42310652 · Full text
BACKGROUND: Tumor cell heterogeneity contributes to melanoma progression, therapeutic resistance, and clinical outcome variability. However, the identity and functional role of specific proliferative subpopulations remai...
BACKGROUND: Tumor cell heterogeneity contributes to melanoma progression, therapeutic resistance, and clinical outcome variability. However, the identity and functional role of specific proliferative subpopulations remain incompletely understood. This study aims to characterize TYRP1-positive melanoma cells and elucidate their role in tumor proliferation, signaling regulation, and treatment response. METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data from primary and metastatic melanoma samples to identify transcriptionally distinct tumor cell subtypes. Functional validation of TYRP1-positive cells was performed using patient-derived organoids, TYRP1-overexpressing melanoma cell lines (A375, SK-MEL-28), and xenograft mouse models. The downstream molecular mechanisms were investigated through gene expression profiling, siRNA-mediated knockdown, recombinant protein treatment, and pathway inhibition assays. Therapeutic responses were assessed using dabrafenib and pembrolizumab treatments. RESULTS: TYRP1 marked a transcriptionally distinct melanoma subpopulation associated with poor patient survival. TYRP1-high organoids and cell lines exhibited significantly enhanced proliferation in vitro and accelerated tumor growth in vivo, without increased metastatic capacity. Mechanistically, TYRP1 induced expression of GPNMB, which activated Notch1 signaling and subsequently upregulated SOX10 and MITF. These transcription factors formed a positive feedback loop with TYRP1 that maintained the proliferative phenotype. GPNMB or Notch1 inhibition disrupted this loop and suppressed tumor growth. Importantly, TYRP1-overexpressing tumors demonstrated resistance to immune checkpoint blockade but increased sensitivity to dabrafenib, suggesting distinct therapeutic vulnerabilities. CONCLUSIONS: Our findings identify TYRP1 as a marker of a highly proliferative melanoma subpopulation that promotes tumor progression through the GPNMB-Notch1-SOX10/MITF axis. The TYRP1-SOX10-MITF feedback loop represents a key driver of melanoma proliferation and a potential biomarker for stratifying therapeutic response, offering a novel avenue for precision treatment in melanoma.
Simultaneous quantification of linezolid and its metabolites (PNU-142300 and PNU-142586) in oral fluid and capillary blood by UPLC-MS/MS: method validation and clinical application using non-invasive sampling techniques.
González-Berdullas P, Cajade-Pascual F, Hermelo-Vidal G … +10 more , Fernández-Castro I, Molinos-Castro S, Bandín-Vilar E, Roca-Sánchez RM, Vázquez-Agra N, Caeiro JR, Zarra-Ferro I, Lendoiro E, Fernández-Ferreiro A, Mondelo-García C
J Transl Med · 2026 Jun · PMID 42310648 · Full text
BACKGROUND: Therapeutic drug monitoring (TDM) can improve the safety and efficacy of the antibiotic linezolid (LZD), particularly in patients at risk of toxicity or with high pharmacokinetic variability. Although oral fl...
BACKGROUND: Therapeutic drug monitoring (TDM) can improve the safety and efficacy of the antibiotic linezolid (LZD), particularly in patients at risk of toxicity or with high pharmacokinetic variability. Although oral fluid (OF) and capillary blood collected through microsampling have emerged as less invasive alternatives to venous blood, the applicability of these matrices for quantifying LZD and its major metabolites-PNU-142300 and PNU-142586-has not been established. This study aimed to develop and validate a UPLC-MS/MS method for the simultaneous quantification of LZD, PNU-142300, and PNU-142586 in OF and capillary blood collected with volumetric absorptive microsampling (VAMS). METHODS: Method validation followed ICH M10 guidelines and included assessment of linearity, accuracy, precision, selectivity, matrix effects, hematocrit influence, dilution integrity, and short- and long-term stability. The method was further evaluated using paired clinical samples from 35 patients receiving LZD. RESULTS: The assay showed linearity from 0.1 to 5 µg/mL for all analytes in plasma, OF, and VAMS, with accuracy and precision within ICH M10 acceptance criteria, demonstrating analytical feasibility across all matrices. In the clinical phase, LZD showed strong correlations with plasma in both VAMS and OF, supporting their feasibility for linezolid monitoring. However, metabolites showed strong but systematically biased correlations in VAMS, indicating that correction factors will be required before routine clinical use. In OF, metabolites were rarely detectable, precluding their monitoring in this matrix. CONCLUSIONS: Overall, these findings demonstrate for the first time the feasibility of using VAMS and OF as non-invasive matrices for LZD TDM. Regarding feasibility, LZD concentrations in both matrices correlated strongly with venous plasma and the method met all ICH M10 validation criteria. Regarding current limitations, direct clinical substitution is not yet possible for metabolite monitoring: systematic underestimation in VAMS requires prospective validation of correction factors, and the near-absence of metabolites in OF limits this matrix to linezolid monitoring only. Larger studies are needed to validate correction strategies and establish matrix-specific therapeutic targets prior to clinical implementation.
Single-cell and spatial analyses reveal endothelial-macrophage inflammatory crosstalk in dry age-related macular degeneration.
Chen Y, Liu C, Chen J … +7 more , Huang Y, Pan G, Wang P, Hu Y, Chen L, Zhang Y, Wang Y
J Transl Med · 2026 Jun · PMID 42304501 · Full text
BACKGROUND: Dry age-related macular degeneration (AMD) is characterized by progressive degeneration of the retinal pigment epithelium-choroid interface, accompanied by immune dysregulation. However, the cellular interact...
BACKGROUND: Dry age-related macular degeneration (AMD) is characterized by progressive degeneration of the retinal pigment epithelium-choroid interface, accompanied by immune dysregulation. However, the cellular interactions and regulatory mechanisms driving macrophage activation in this process remain incompletely understood. METHODS: We integrated spatial transcriptomics and single-cell RNA sequencing data from a photo-oxidative damage mouse model and human dry AMD samples. A series of bioinformatic analyses, including cell-cell communication analysis, enrichment analysis, and pseudotime trajectory analysis, were performed to characterize cellular features and regulatory pathways. RESULTS: In the photo-oxidative damage mouse model, the RPE-choroid region showed marked infiltration of myeloid cells. In human dry AMD samples, SLC16A10-positive macrophages were enriched and exhibited pro-inflammatory features. Further analysis revealed that endothelial cells regulate SLC16A10-positive macrophages through the TNFSF10-TNFRSF10B pathway, with NFKB1 acting as a key regulator to activate NF-κB signaling, thereby promoting the formation of a vascular-immune inflammatory niche. CONCLUSIONS: This study systematically characterizes immune remodeling in the RPE-choroid region in dry AMD and identifies an endothelial-macrophage TNFSF10-TNFRSF10B-NF-κB signaling pathway that drives disease progression. These findings provide new insights into disease mechanisms and suggest potential therapeutic targets for dry AMD.
tRF and gastric cancer: molecular mechanism exploration and novel strategies for precision diagnosis and therapy.
Jia H, Duan Y, Huang Y … +6 more , Hu J, Fan X, Gong R, Zhang N, Qin R, Wang H
J Transl Med · 2026 Jun · PMID 42304486 · Full text
BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality, and current diagnostic biomarkers lack sufficient sensitivity and specificity. tRNA-derived fragments (tRFs), an emerging class of non-...
BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality, and current diagnostic biomarkers lack sufficient sensitivity and specificity. tRNA-derived fragments (tRFs), an emerging class of non-coding RNAs, have garnered attention for their stability and regulatory roles in carcinogenesis. MAIN BODY: This review adopts a comparative perspective to evaluate the distinctive roles of tRFs in GC relative to other non-coding RNAs, particularly microRNAs (miRNAs). We summarize tRF biogenesis and classification, highlighting their unique mechanistic repertoire that encompasses both AGO2-dependent gene silencing and non-canonical protein interactions. Dysregulated tRF profiles in patient samples reveal promising diagnostic candidates (e.g., tRF-23-Q99P9P9NDD, tRF-17-18VBY9M) that demonstrate superior performance to conventional markers. However, we critically examine translational barriers including functional heterogeneity, detection challenges, and the absence of registered clinical trials. We also dissect sources of contradictory findings and propose standardized frameworks for future investigation. CONCLUSIONS: tRFs represent functionally versatile regulators with distinct advantages over miRNAs in diagnostic applications. Their clinical translation requires overcoming methodological standardization gaps and evidence thresholds through interdisciplinary efforts integrating multi-omics profiling, advanced delivery systems, and rigorous clinical validation.
A novel therapeutic monoclonal antibody targeting PZR demonstrates potent anti-metastatic efficacy in triple-negative breast cancer.
Chen J, Shao J, Huang J … +10 more , Ye L, He S, Qin Y, Tian Z, Liu X, He L, Cao J, Li L, Gu H, Wu G
J Transl Med · 2026 Jun · PMID 42304484 · Full text
BACKGROUND: Metastasis is the leading cause of mortality in triple-negative breast cancer (TNBC). PZR, a member of the immunoglobulin super-family, promotes the migration, invasion, and metastasis of cancer cells. Whethe...
BACKGROUND: Metastasis is the leading cause of mortality in triple-negative breast cancer (TNBC). PZR, a member of the immunoglobulin super-family, promotes the migration, invasion, and metastasis of cancer cells. Whether targeting PZR can inhibit TNBC dissemination remains unclear. In this study, we developed a novel anti-PZR monoclonal antibody (mAb) and humanized it to explore its impact on TNBC metastasis. METHODS: Recombinant PZR-ECD protein was used to generate anti-PZR monoclonal antibodies, whose binding affinity was evaluated by SPR. Their effects on cell migration were assessed via Trans-well assays. Antibody specificity was confirmed by western blotting, Co-IP, and FACS. PZR mediated TNBC cell interactions with the ECM were examined through cell adhesion experiments. The therapeutic efficacy of the PZR antibody was evaluated in a TNBC metastasis mouse model. RESULTS: Our findings revealed that the mouse anti-PZR mAb (12F6) exhibited high-affinity binding to the recombinant PZR protein. The 12F6 mAb specifically recognized the native PZR protein expressed by TNBC cells and was efficiently internalized by PZR-positive TNBC cells. Furthermore, 12F6 significantly inhibited the migration and metastasis of PZR-positive TNBC cells in both in vitro and in vivo settings. PZR was found to interact with integrin β1, promoting the fibronectin-dependent adhesion and FAK activation of TNBC cells. The humanized 12F6 antibody (Hu12F6) maintained comparable binding affinity to PZR in comparison with the parental 12F6 antibody and effectively inhibited the migration and metastasis of PZR-positive TNBC cells in both in vitro and in vivo experiments. CONCLUSIONS: The results of our study support a model by which PZR interacting with integrin β1 enhances fibronectin-dependent integrin signaling and biological functions. Hu12F6 by blocking the interaction between PZR and integrin β1 may offer a novel therapeutic strategy to treat PZR-positive metastatic cancers including TNBC.
Integrative spatiotemporal transcriptomics identifies a liver metastasis-related initial cell population associated with the SEMA3A-NRP1 axis in pancreatic ductal adenocarcinoma.
Li Y, Liu YD, Jiang ZY … +1 more , Lu HX
J Transl Med · 2026 Jun · PMID 42304476 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which liver metastasis represents the principal determinant of poor prognosis. Although metastatic dissemination is thought to be drive...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which liver metastasis represents the principal determinant of poor prognosis. Although metastatic dissemination is thought to be driven by highly plastic tumor cells, the transcriptional features of liver metastasis-related initial cell (LMIC) and its spatial crosstalk with the metastatic microenvironment during PDAC progression remain incompletely defined. METHODS: We integrated bulk transcriptomic, single-cell RNA sequencing, and 10x Genomics spatial transcriptomic datasets from multiple clinical cohorts. Malignant epithelial cells were accurately identified using a machine learning-based approach (scMalignantFinder). Developmental trajectory inference algorithms (VECTOR, scTour, and Monocle2) were applied to define LMIC. Intercellular communication was interrogated using CellChat and CellPhoneDB, while spatial ecological niches were resolved using RCTD and MISTy. Functional validation of key signaling axes was performed by immunohistochemistry (IHC), wound-healing assays, and Transwell invasion assays. RESULTS: We identified a TSPAN1_MC2 subpopulation of malignant epithelial cells with high differentiation potential and further characterized LMIC located at the origin of the developmental trajectory, characterized by concurrent epithelial-mesenchymal transition (EMT) and stemness features. The LMIC population exhibited elevated expression of stemness-associated genes, including NRP1 and NRP2, and was significantly associated with poor clinical outcomes and resistance to immunotherapy. Cell-cell communication and spatial analyses revealed that cancer-associated fibroblasts (CAFs) secrete SEMA3A, which engages NRP1 on LMIC, mediating their spatial co-localization and functional reprogramming. In vitro assays supported that over-expression of SEMA3A and NRP1 could enhance PDAC cell migration and invasion. The transcription factor YY1 was nominated as a potential regulatory associated with the LMIC transcriptional program, showing structural alignment with NRP1 expression and the activation of pathways such as WNT and PI3K-AKT signaling. In addition, the LMIC phenotype displayed pronounced lipid metabolic reprogramming, with up-regulation of rate-limiting enzymes including FASN and ACACA. Pharmacogenomic simulations further suggested a potential correlation with heightened sensitivity of the LMIC population to FAK inhibitors (PF-562271) and HDAC inhibitors (Mocetinostat), suggesting hypothetical therapeutic vulnerabilities. CONCLUSIONS: At single-cell resolution, this study characterizes the LMIC population in PDAC and implicates a CAF-associated SEMA3A-NRP1 signaling axis within their spatial and functional microenvironmental niches. These findings provide a refined conceptual framework for the development of prospective targeted strategies aimed at disrupting early microenvironmental cross-talk associated with PDAC liver metastasis.
Proteomic and machine learning analysis predicts treatment response signatures in Myasthenia Gravis.
Gilbert K, Cheema AK, Kaminski HJ … +1 more , Kusner LL
J Transl Med · 2026 Jun · PMID 42304472 · Full text
BACKGROUND: Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease with variable treatment responses with a need for biomarkers to guide therapeutic decision making. Proteomic profiling, coupled wi...
BACKGROUND: Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease with variable treatment responses with a need for biomarkers to guide therapeutic decision making. Proteomic profiling, coupled with machine learning, offers a hypothesis-free approach to identify multi-protein signatures associated with treatment response. METHODS: We analyzed sera collected at entry (baseline) from participants in a phase 3 trial randomized trial comparing thymectomy plus prednisone versus prednisone alone, along with matched controls using liquid chromatography-mass spectrometry. We derived disease-specific proteomic signatures and evaluated associations between baseline proteins and 6-month clinical outcomes using multiple machine-learning approaches with internal validation. RESULTS: Baseline serum proteomes distinguished MG from controls, with pathway enrichment implicating complement activation, immunoglobulin production, and T-cell receptor signaling. Distinct protein panels predicted 6-month clinical improvement within each treatment arm. In the thymectomy-plus-prednisone group, models captured non-linear relationships of predictive proteins in contrast with the predominant additive patterns observed in the prednisone-alone group. Predictive proteins were enriched for T-cell signaling and leukocyte trafficking functions, providing insight into treatment-specific biology. CONCLUSIONS: Baseline serum proteomics captures core disease characteristics of MG and predicts short-term clinical response in a treatment-specific manner. While our results require validation in independent cohorts, these findings could enable biomarker-guided selection of thymectomy, refine risk stratification, and furnish mechanistic readouts for future MG trials and clinical care. We aim to conduct future studies using -omic approaches to validate these baseline predictive biomarkers and pathways of treatment response in patients with MG.
Roles and therapeutic prospects of the laminin family in disorders of the nervous system.
Zhang X, Li X, Gao L … +8 more , Qiao Y, Lv B, Zhang Q, Zhang M, Yu J, Li H, Bi H, Ding Y
J Transl Med · 2026 Jun · PMID 42304470 · Full text
BACKGROUND: Neurological disorders comprise a heterogeneous spectrum-including cerebrovascular disease, neurodegeneration, autoimmune demyelination, neuropsychiatric conditions, and trauma-whose incidence and prevalence...
BACKGROUND: Neurological disorders comprise a heterogeneous spectrum-including cerebrovascular disease, neurodegeneration, autoimmune demyelination, neuropsychiatric conditions, and trauma-whose incidence and prevalence are rising with population aging, creating sustained healthcare and socioeconomic burdens. Recent work highlights laminin, a major non-collagenous BM glycoprotein, as a key regulator of central nervous system structure and function. As a core extracellular matrix scaffold and signaling hub, laminin orchestrates matrix remodeling, barrier disruption/repair, neuroinflammation, and neuronal plasticity; it contributes to neurodevelopment and axon guidance, synaptogenesis and plasticity, myelination and nodal microarchitecture, and the homeostasis of the blood-brain barrier and neurovascular unit. METHODS: Based on a comprehensive literature review, this article systematically elaborates the structure and classification of laminin, its spatiotemporal distribution and physiological roles in the central nervous system, as well as the molecular mechanisms and network effects in neurological diseases. Furthermore, it evaluates the feasibility and challenges of laminin-targeted therapies, aiming to provide insights for the development of innovative precision interventions. CONCLUSION: This review systematically demonstrates that the laminin family functions not merely as a "structural hub of the basement membrane," but also holds substantial promise as an "actionable target" for neurological disorders. Through a parallel receptor network comprising integrins, α-dystroglycan, and heparan sulfate proteoglycans/syndecans, laminin couples mechanical support with signal transduction, occupying a central position in the development, homeostatic maintenance, and repair of the blood-brain barrier/neurovascular unit, synaptic architecture, and the myelin-Nodes of Ranvier microstructure. Future investigations should elucidate the profound mechanistic roles of laminin family members in neurological diseases and advance targeted therapeutic development, thereby facilitating novel strategies for the prevention and treatment of neurological disorders.
Innovative multi-epitope vaccine engineering for dual protection against Salmonella and Shigella leveraging FliC flagellin protein adjuvant properties: an immunoinformatics-based approach.
Afshari E, Soleimani N
J Transl Med · 2026 Jun · PMID 42304404 · Full text
BACKGROUND: Shigellosis and salmonellosis are prominent food-borne illnesses associated with high mortality rates and morbidity, for which, as of now, no licensed vaccine is available. Multiple epitope vaccines offer pro...
BACKGROUND: Shigellosis and salmonellosis are prominent food-borne illnesses associated with high mortality rates and morbidity, for which, as of now, no licensed vaccine is available. Multiple epitope vaccines offer promising prospects as alternatives to conventional vaccines by combining extremely immunogenic as well as conserved epitopes to overcome weaknesses related to weak antigens as well as serotype specificity. METHODS: For the first time, this study focused on developing a new protective multiepitope vaccine for dual protection against Salmonella and Shigella by integrating six conserved virulence factors: SpvB, SipD, RcK, SigA, IpaD, and FimA. RESULTS: When immunoinformatics tools were applied, highly conserved B- and T-cell epitopes with broad HLA allele coverage and high antigenicity were predicted, while allergenicity and toxicity assessments were used to assess safety. The selected epitopes were conjugated with suitable spacers to maintain structural integrity and increase immune processing. The conserved domain of the Salmonella flagellin protein (FliC) was used as both the scaffold and the TLR5 agonist adjuvant. Secondary and tertiary FliC-based multiepitope construct (FMEC) structures were predicted, refined, and validated; these structures exhibited desirable physicochemical properties, such as stability, hydrophilicity, and thermal resilience, with a molecular weight of 33 kDa, which is ideal for vaccine construction. In addition, ProSA and Ramachandran plot validation confirmed the reliability of the FMEC model. Immune simulation demonstrated powerful cellular and humoral immunity, whereas molecular docking and normal mode analysis confirmed the stable interaction of FMEC with the TLR4/5 or MHCI/MHCII receptors. CONCLUSION: Although FMEC shows promise as a safe, nontoxic, nonallergen, and widely immunogenic multiepitope vaccine candidate to combat Salmonella and Shigella, further experimental validation needs to be carried out to ascertain its in vivo protective efficacy. TRIAL REGISTRATION: Not applicable.
The mitochondrial GTPase ERAL1 inhibits HBV replication by triggering the MAVS signaling cascade.
Lin C, Zheng X, Chen K … +10 more , Ran N, Luo L, Zhang X, Huang Y, Zhang J, Zhu H, He J, Yang B, Ou Q, Liu C
J Transl Med · 2026 Jun · PMID 42304389 · Full text
BACKGROUND AND AIMS: Mitochondrial GTPase ERA G-protein-like 1 (ERAL1) is considered an antiviral host factor against RNA viruses. However, its role in driving DNA virus infection, particularly hepatitis B virus (HBV) in...
BACKGROUND AND AIMS: Mitochondrial GTPase ERA G-protein-like 1 (ERAL1) is considered an antiviral host factor against RNA viruses. However, its role in driving DNA virus infection, particularly hepatitis B virus (HBV) infection, and its relevance to human liver disease are unknown. This study aimed to define the function and molecular mechanism of ERAL1 in HBV pathogenesis. METHODS: Complementary models, including HBV-replicating cell lines, an rAAV8-HBV hydrodynamic mouse model, and clinical samples from patients across the natural history of chronic HBV infection were employed and analyzed via coimmunoprecipitation, confocal immunofluorescence, RNA sequencing, qPCR, immunoblotting, and immunohistochemistry. RESULTS: ERAL1 expression was significantly suppressed in HBV patients, including an approximately 75% reduction in the livers of patients during the immune-reactive phase compared with those in healthy controls. ERAL1 overexpression resulted in notable antiviral activity, suppressed HBV replication and achieved nearly 60% HBsAg clearance in vivo. Mechanistically, ERAL1 interacts with mitochondrial adaptor MAVS, promoting its aggregation and subsequently activating the downstream Akt and MAPK signaling pathways, which are essential for its antiviral effect. CONCLUSIONS: ERAL1 is identified as a crucial HBV-restricting host factor and a novel mitochondria-centered defense mechanism in which ERAL1 reinforces MAVS-dependent antiviral signaling. The notable downregulation of ERAL1 in patient livers and its considerable antiviral effectiveness suggest that ERAL1 is a candidate host factor worthy of further therapeutic exploration.
Role of spectral CT in quantitative evaluation of pathologic response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma: a pilot study.
Zheng H, Zhu Y, Li M … +5 more , Zhang Q, Wei X, Chen X, Ren W, Liu S
J Transl Med · 2026 Jun · PMID 42304386 · Full text
BACKGROUND: To find a useful non-invasive biomarker for evaluating treatment response to neoadjuvant immunochemotherapy (nICT) in patients with esophageal squamous cell carcinoma (ESCC), using spectral computed tomograph...
BACKGROUND: To find a useful non-invasive biomarker for evaluating treatment response to neoadjuvant immunochemotherapy (nICT) in patients with esophageal squamous cell carcinoma (ESCC), using spectral computed tomography (CT). METHODS: Spectral CT-derived parameters including the 40 keV virtual monoenergetic imaging (VMI), iodine concentration (IC), and normalized iodine concentration (NIC) were obtained before and after nICT in 87 patients with ESCC. Independent samples t-test (normality) or Mann-Whitney U test (non-normality) was used to compare the differences of spectral CT-derived parameters between responders and non-responders. Binary logistic regression analysis was performed to identify independent predictive factors for responders. Diagnostic performance of parameters in predicting response was tested with receiver operating characteristic (ROC) curve analysis. RESULTS: The post-area, post-40 keV VMI, post-IC, and post-NIC of the responders were significantly lower than those of the non-responders (p < 0.001, < 0.001, < 0.001, and 0.002, respectively). Post-area (odds ratio [OR], 0.980, 95% confidence interval [95% CI], 0.970-0.990; p < 0.001) and post-NIC (OR, 0.824, 95% CI, 0.723-0.938; p = 0.003) were independent post-treatment predictors of therapeutic efficacy. A predictive model combining post-NIC and post-area showed the most favorable diagnostic performance with an area under the curve of 0.844. CONCLUSIONS: Post-NIC and post-area of tumor might serve as independent monitoring biomarkers for assessing pathological response to nICT in ESCC. The model combining post-NIC and post-area may provide preliminary imaging evidence for individualized clinical decisions.
Single-cell and spatial transcriptomes reveal oligodendrocyte remodeling fatty acid metabolism microenvironment of lung cancer brain metastases.
Yang Y, Gao Y, Qi Z … +11 more , Li S, Wang Z, Li D, Chen L, Zhou C, Feng M, Chen X, Hao B, Wu X, Li L, Cao Y
J Transl Med · 2026 Jun · PMID 42304367 · Full text
BACKGROUND: Brain metastases represent a prevalent and lethal complication in advanced lung cancer, where the brain microenvironment is pivotal in facilitating metastatic tumor progression. Recent findings indicate the p...
BACKGROUND: Brain metastases represent a prevalent and lethal complication in advanced lung cancer, where the brain microenvironment is pivotal in facilitating metastatic tumor progression. Recent findings indicate the presence of oligodendrocyte infiltration within lung cancer brain metastases (LCBM). Lipid metabolic reprogramming has emerged as a critical feature of the brain metastatic niche, influencing both tumor cell survival and immune cell function. This study aimed to determine whether oligodendrocytes undergo lipid metabolic reprogramming in LCBM and whether their derived fatty acids functionally promote tumor proliferation and immune modulation. METHODS: Single cell RNA sequencing (ScRNA-seq), spatial transcriptome sequencing, lipidomics, and lipid tracing techniques to comprehensively analyze metabolic alterations in oligodendrocytes and their dynamic interactions with tumor and immune cells. Western blotting, qPCR and multiple immunofluorescence staining were used to detect the expression of fatty acid synthesis enzymes in oligodendrocytes and immunosuppressive markers in macrophages. RESULTS: Analysis of independent scRNA-seq datasets revealed markedly increased lipid synthesis activity in oligodendrocytes within LCBM. Hypoxic conditions and co-culture with metastatic lung cancer cells further enhanced the expression of fatty acid synthases in oligodendrocytes. Spatial transcriptomics and scRNA-seq indicated that tumor cells and macrophages were major recipients of oligodendrocyte-derived fatty acids, exhibiting enhanced uptake and degradation. Treatment with oligodendrocyte-conditioned medium significantly increased the expression of fatty acid uptake proteins in tumor cells and macrophages. Furthermore, oligodendrocyte-derived fatty acids supported tumor cell proliferation and polarized macrophages toward an immunosuppressive phenotype. Notably, scRNA-seq identified a macrophage subpopulation (Mac_FABP4) as a candidate mediator of lipid-driven immune suppression. CONCLUSION: These findings delineate the pivotal role of oligodendrocytes in LCBM, revealing their contribution of lipids that enhance tumor proliferation and induce immunosuppression, thereby suggesting that glial lipid metabolism may represent a potential therapeutic target warranting further investigation.
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