Journal of Translational Medicine最新文献

{"title":"Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.","authors":"Yinping Wang, Weijie Chen, Zida Wang, Siwen Cai, Xinnan Zhao, Jingsi Jin, Ting Gao, Junwen Qu","doi":"10.1186/s12967-025-07069-y","DOIUrl":"10.1186/s12967-025-07069-y","url":null,"abstract":"<p><strong>Background: </strong>Immunometabolic adaptations may induce tumor immune escape and immunotherapeutic resistance, representing crucial mechanisms in cancer progression. Understanding the metabolic rewiring of tumor-infiltrating immune cells as tumors advance could enhance current immune-oncology treatments.</p><p><strong>Methods: </strong>In this study, we investigated metabolic heterogeneity in immune cells within both tumor and adjacent normal tissue using single-cell transcriptome profiling of colon cancer. We also utilized the MC38 colorectal cancer model, a commonly employed mouse tumor model, to assess the metabolic atlas of major immune cell populations in tumor and normal tissue.</p><p><strong>Results: </strong>We examined the immunometabolic features in tumor tissue and adjacent normal tissue using public single-cell transcriptomic datasets of colorectal cancer (CRC) patients, in which myeloid cells showed dominant metabolic activity. Using a mouse tumor model, we demonstrated distinct metabolic reprogramming of major immune cell types in tumor compared to normal tissue. Specifically, we observed increased glucose and lipid uptake, along with abundant lipid accumulation in tumor-infiltrating myeloid cells, particularly macrophages. Additionally, we identified diverse mitochondrial fitness and oxidative stress levels within the tumor immune microenvironment. Macrophages exhibited metabolic fitness, CD8⁺ T cells displayed mitochondrial depolarization, and neutrophils showed high oxidative stress. Furthermore, we investigated immunometabolic dynamics and observed augmented metabolic activity in immune cells infiltrating progressive and late stages of tumor development. Notably, intratumoral macrophages exhibited metabolic heterogeneity, characterized by robust lipid uptake and synthesis, which correlated with a pro-tumor phenotype and poor clinical outcomes.</p><p><strong>Conclusion: </strong>Overall, our study unveils the heterogeneity and dynamics of metabolic properties in immune cells within the tumor microenvironment. These findings provide insights for developing therapeutic strategies that target metabolism to enhance antitumor immunity.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1055"},"PeriodicalIF":7.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel anti-PD-L1/IL-8 bispecific antibody BP2402 enhances antitumor immunity and modulates inflammatory signaling in triple-negative breast cancer mice model.","authors":"Liying Song, Sumin Tang, Xuelei Pi, Yuanyuan Yan, Chenxi Hu, Liang Liu, Hongna Chen, Yating Zhang, Shishi Liu, Dan Yu, Chengkai Yin, Tianyan Liu, Xu Li, Deshan Li, Zhenzhong Wang, Wei Zhu, Kaiyuan Hui, Zhihang Liu, Xiaodong Jiang","doi":"10.1186/s12967-025-07105-x","DOIUrl":"10.1186/s12967-025-07105-x","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Immune checkpoint inhibitors targeting the programmed death-ligand 1 (PD-L1) pathway show restricted efficacy in TNBC, with response rates of only 5-10% as monotherapy. Interleukin-8 (IL-8/CXCL8) signaling promotes immunosuppression and mediates resistance to anti-PD-L1 therapy, necessitating combination approaches to overcome these limitations. However, the underlying mechanisms of enhanced efficacy from dual pathway targeting require further investigation.</p><p><strong>Methods: </strong>We generated humanized mouse models by reconstituting immunodeficient mice with human PBMCs from five donors (n = 5 mice/group). MDA-MB-231 TNBC cells were implanted subcutaneously, and mice were treated with vehicle control, atezolizumab (anti-PD-L1), HuMax-IL8 (anti-IL-8), combination therapy, or a novel bispecific antibody BP2402 targeting both PD-L1 and IL-8. Antitumor activity was assessed alongside single-cell RNA sequencing of tumors and mechanistic analyses including immunofluorescence and Western blot.</p><p><strong>Results: </strong>Combination therapy demonstrated significantly enhanced tumor growth inhibition compared to atezolizumab monotherapy in responsive donor models (51.28% vs. 39.13% for donor 3, p < 0.01; 44.01% vs. 6.57% for donor 4, p < 0.01). Single-cell RNA sequencing showed higher intratumoral T-cell fractions with combination therapy (donor 3: 80.5% vs. 26.7%; donor 4: 63.6% vs. 13.0% compared to control). BP2402 maintained high binding affinity for both IL-8 (KD = 2.132 nM) and PD-L1 (KD = 1.473 nM), and demonstrated superior antitumor efficacy compared to monotherapies (p < 0.001 vs. vehicle, p < 0.01 vs. individual antibodies). BP2402 treatment significantly reduced CXCL8 and VEGFA expression, suppressed JAK1/STAT1 signaling pathway activation, and upregulated pro-apoptotic proteins including FAS and BAX while effectively modulating T cell exhaustion markers PD-1 and TIM-3.</p><p><strong>Conclusions: </strong>These results indicate that dual targeting of PD-L1 and IL-8 pathways represents a promising therapeutic strategy for TNBC. The bispecific antibody approach offers superior therapeutic potential by simultaneously modulating immune checkpoints, inflammatory signaling, and angiogenesis, effectively addressing resistance mechanisms. Additional preclinical optimization and clinical studies are required to fully assess the therapeutic potential of this novel immunotherapeutic approach.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1056"},"PeriodicalIF":7.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application and clinical utility assessment of natural language processing-based software for copy-number variants interpretation.","authors":"Songchang Chen, Chang Liu, Xiaorui Luan, Yuling Wang, Yuexin Xu, Yunshuang Li, Fenjiao Zhang, Weihui Shi, Xuanyou Zhou, Chenming Xu","doi":"10.1186/s12967-025-07063-4","DOIUrl":"10.1186/s12967-025-07063-4","url":null,"abstract":"<p><strong>Background: </strong>Manual interpretation of copy-number variant (CNV) according to the guideline published by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resources (ClinGen) in 2020 is labor-intensive and time-consuming. The application of natural language processing (NLP)-based software like CNVisi can reduce the burden of CNV interpretation, but its clinical utility needs to be further evaluated.</p><p><strong>Methods: </strong>We firstly used 1000 CNVs which had been previously manually classified to assess the performance of CNVisi. To assess the clinical utility of CNVisi, we collected 5861 CNVs from 2443 next-generation sequencing (NGS)-based CNV sequencing (CNV-seq) samples. The CNVs were first classified by CNVisi and then reviewed by genetic experts. After removing duplicates, the remaining 3384 CNVs were used for assessment of classification consistency, and 154 CNVs that met the reporting rules were finally selected for further analysis.</p><p><strong>Results: </strong>The overall accuracy of CNVisi in distinguishing pCNVs (Pathogenic or Likely Pathogenic CNVs) was 97.7% (977/1000) in preliminary assessment of performance. And the accuracy of CNVisi in assessment of clinical utility was 99.6% (3370/3384). Among 154 CNVs that met clinical reporting rules, 23 CNVs were classified with disagreement between CNVisi and genetic experts. The inconsistency in classification is mainly caused by the overlap between CNV and low-penetrance regions, and the difference in scoring of evidence related to the literature. According to the reporting rules, total CNVs were classified with a high consistency of 98.6% (5781/5861) between genetic experts and CNVisi, and the CNV-seq results of 96.9% (2367/2443) samples could be accurately and efficiently interpreted by CNVisi. Furthermore, CNVisi was superior to previous tools for CNV interpretation and classification, and showed excellent clinical utility.</p><p><strong>Conclusions: </strong>Applying CNV interpretation software such as CNVisi with clinical utility can reduce the burden of genetic experts and improve the efficiency of CNV interpretation.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1052"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage polarization in diabetic vascular complications: mechanistic insights and therapeutic targets.","authors":"Liyuan Cao, Lu Ding, Qinjing Xia, Zepeng Zhang, Min Li, Siyu Song, Kai Yin, Zirui Li, Xueyan Li, Zihan Wang, Daqing Zhao, Xiangyan Li, Zeyu Wang","doi":"10.1186/s12967-025-07075-0","DOIUrl":"10.1186/s12967-025-07075-0","url":null,"abstract":"<p><p>Diabetes mellitus, particularly type 2 diabetes mellitus, is a widespread chronic metabolic disorder characterized by persistent hyperglycemia and low-grade chronic inflammation. This sustained inflammatory state is a major driver of both macrovascular and microvascular complications. Among immune cells, macrophages play a central role as effectors and regulators of chronic inflammation. In the diabetic milieu, they respond to diverse microenvironmental cues and polarize into distinct functional phenotypes, thereby contributing to both the progression and potential resolution of diabetes-associated vascular damage. This review examines the mechanisms of macrophage polarization in diabetic vascular complications, elucidates key signaling pathways and their interactions with metabolic dysfunction, and summarizes current regulatory strategies and emerging therapeutic targets. Particular emphasis is placed on recent pharmacological approaches that modulate macrophage polarization, highlighting their potential as novel strategies to delay or prevent the onset and progression of vascular complications in diabetes.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1050"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MNDA promotes immunosuppression in microsatellite instability-high colorectal cancer by facilitating PMN-MDSC infiltration via H3K18 lactylation.","authors":"Xuan Zhang, Wen-Bin Wang, Xin-Yi Cai, Xiao-Qiong Chen, Qing Feng, Quan Yang, Ji-Biao Li, Wei Xiong, Tao Wu","doi":"10.1186/s12967-025-07097-8","DOIUrl":"10.1186/s12967-025-07097-8","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) have demonstrated significant clinical benefit in colorectal cancer (CRC) with microsatellite instability-high (MSI-H) status, yet a substantial subset of patients remains resistant to therapy. Understanding the mechanisms of resistance and identifying new therapeutic targets are urgently needed.</p><p><strong>Methods: </strong>We established a murine MC38-based MSI-H CRC model to investigate the variability in PD-1 treatment response and performed single-cell RNA sequencing (scRNA-seq) on tumors from patients with PD-1-sensitive and PD-1-resistant CRC. Immune cell subsets and signaling pathways were analyzed using CellChat and AUCell, and gene expression enrichment was performed. Functional assays, including RNA-seq, ChIP-seq, qRT-PCR, and Co-IP, were employed to characterize the role of MNDA and its downstream targets.</p><p><strong>Results: </strong>scRNA-seq analysis revealed a significant enrichment of polymorphonuclear neutrophil myeloid-derived suppressor cells (PMN-MDSCs) in PD-1-resistant MSI-H CRC, accompanied by increased lactylation activity and high MNDA expression. Further investigations revealed that MNDA recruits the histone acetyltransferase EP300 to the CXCR2 promoter, mediating H3K18 lactylation and enhancing CXCR2 transcription. This promotes PMN-MDSC infiltration and the establishment of an immunosuppressive microenvironment, thereby impairing PD-1 efficacy. Inhibition of the MNDA/EP300-CXCR2 axis reversed H3K18la modification, reduced PMN-MDSC infiltration, remodeled the immune microenvironment, and restored sensitivity to PD-1 therapy.</p><p><strong>Conclusions: </strong>Our study reveals a novel mechanism by which MNDA-driven H3K18 lactylation of the CXCR2 promoter facilitates immune evasion and PD-1 resistance in MSI-H CRC. Targeting the MNDA/EP300-CXCR2 regulatory axis represents a promising strategy for overcoming ICI resistance and enhancing the therapeutic benefit in CRC.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1049"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of iron deficiency on therapeutic outcomes in colorectal cancer patients: a single-center cohort study.","authors":"Yajun Luo, Ping Zheng, Hao Luo, Xin Chen, Ke Zhang, Wuyi Wang, Bo Song, Chao Liu, Lubei Rao, Hui Yang, Xuan Zhang, Qingmei Huang, Haiyang Zhou, Hai Hu","doi":"10.1186/s12967-025-07018-9","DOIUrl":"10.1186/s12967-025-07018-9","url":null,"abstract":"<p><strong>Background: </strong>Iron deficiency (ID) exhibits strikingly high prevalence in colorectal cancer (CRC), yet its prognostic implications remain insufficiently characterized. This study aimed to evaluate the association between pre-treatment ID status and therapeutic outcomes in patients undergoing standardized treatment protocols for CRC.</p><p><strong>Methods: </strong>A retrospective cohort of 1003 CRC patients was analyzed to assess the prevalence of ID and its correlations with clinicopathologic features, postoperative recovery, neoadjuvant therapy response, and iron metabolism and ferroptosis-related gene expression. The association of ID with clinicopathologic data, laboratory parameters, and treatment patient outcome was analyzed using logistic regression. Prussian blue staining was used to assess iron levels in tumor and adjacent noncancerous tissues. Bioinformatics was employed to analyze the expression levels of iron metabolism and ferroptosis-related genes.</p><p><strong>Results: </strong>ID was identified in 50.85% (510/1003) of patients. Compared with non-ID patients, those with ID exhibited higher female predominance (56.8% vs. 43.2%), significant increased prevalence of anemia (76.2% vs. 23.8%), and elevated levels of C-reactive protein (CRP), along with decreased albumin (Alb) levels. Clinicopathologic associations with ID included larger tumor diameter, more advanced pathological T/N/M stages, poorer tumor differentiation, and increased lymphovascular and perineural invasion. Among patients received neoadjuvant therapy, ID was associated with higher clinical T/N stages and lower tumor regression grades. Postoperatively, ID patients experienced significantly longer time to first flatus, lower albumin levels, and elevated inflammatory markers. Prussian blue staining revealed reduced iron content in both tumor and adjacent tissues of ID patients. Molecular analyses identified dysregulated iron metabolism genes, with DMRT1, HAMP, FTH1, FTL, TFRC, LCN2, PCBP1 and PCBP2 upregulated and ACO1, IRPEB2, OTUD1, SLC40A1 and NCOA4 downregulated in tumor tissues. Ferroptosis suppressor genes (LCN2, TFRC and SLC40A1) were overexpressed in non-responders to chemoradiotherapy.</p><p><strong>Conclusion: </strong>ID is closely associated with aggressive tumor biology, suboptimal response to neoadjuvant therapy, and impaired postoperative recovery. Dysregulation of iron homeostasis and ferroptosis pathways in ID patients may contribute to CRC progression. These findings highlight ID as a potential biomarker for risk stratification and suggest that targeting iron metabolism could improve therapeutic outcomes in CRC management.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1051"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA signatures of cancer risk in kidney transplant patients: insights from the COMETA study.","authors":"Mariadelina Simeoni, Rossella Tufano, Valeria Grandinetti, Alessia Maria Cossu, Carlo Alfieri, Rosamaria Pollastro, Antonello Calcutta, Marianna Scrima, Marco Bocchetti, Silvia Zappavigna, Ines Simeone, Giuseppe Grandaliano, Anna Capasso, Piergiorgio Messa, Giuseppe Castellano, Alberto Mella, Luigi Biancone, Michele Ceccarelli, Michele Caraglia, Gaetano La Manna, Giovambattista Capasso, Franco Citterio","doi":"10.1186/s12967-025-07030-z","DOIUrl":"10.1186/s12967-025-07030-z","url":null,"abstract":"<p><strong>Background: </strong>Post-transplant malignancies are one of the leading causes of morbidity, mortality and graft failure in kidney transplant recipients (KTRs). While viral infections and immunosuppressive drugs have historically been considered primary causes, the mechanisms underlying post-transplant cancer occurrence remain incompletely understood. Furthermore, predictive cancer biomarkers have yet to be identified in KTRs.</p><p><strong>Methods: </strong>COMETA study is an observational study involving 138 KTRs, and it aims to elucidate the interplay between the immune system and cancer by integrating comprehensive clinical data with high-throughput small-RNA sequencing on the serum of patients with post-kidney transplant malignancies.</p><p><strong>Results: </strong>Our results identified three distinct serum miRNA profiles, respectively, associated with kidney transplantation, pro-oncogenic and onco-protective factors in this unique population. These profiles were also used to create miRNA classifiers, which demonstrated promising predictive performance, especially for tumor-promoting signatures. Notably, miR-210-3p up-regulation, within the cancer-related profile was first found to be associated with non-melanoma skin cancer.</p><p><strong>Conclusion: </strong>These findings could serve as a basis for future research, paving the way for the development of advanced tools for early cancer diagnosis, precise prognosis formulation, and the creation of targeted therapies for KTRs with neoplastic complications.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1053"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomaterials and cell-based therapy post spinal cord injury.","authors":"Sara Haratizadeh, Haitao Liu, Hengde Li, Mohsen Adeli, Angelo H All","doi":"10.1186/s12967-025-06974-6","DOIUrl":"10.1186/s12967-025-06974-6","url":null,"abstract":"<p><p>Spinal cord injury (SCI) imposes a significant physical, social, and economic burden on millions of patients and their families worldwide. Although medical and surgical care improvements have decreased mortality rates, sustained recovery remains constrained. Cell-based therapies offer a promising strategy for neuroprotection and neuro-regeneration post-SCI. This article reviews the most promising preclinical approaches, encompassing the transplantation of embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), oligodendrocyte progenitor cells (OPCs), Schwann cells (SCs), and olfactory ensheathing cells (OECs), along with the activation of endogenous pluripotency cell banking strategies. We also outline key ancillary strategies to enhance graft cell viability and differentiation, such as trophic factor assistance, engineered biomaterials for supportive scaffolds, and innovative methods for a synergistic effect in treatment, including promoting neuronal regeneration and reducing glial scars. We highlight the key aspects of SCI pathophysiology, the fundamental biology of cell treatments, and the advantages and limitations of each approach.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1042"},"PeriodicalIF":7.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBP/p300, a promising therapeutic target for prostate cancer.","authors":"Hongtao Xu, Yifan Hou, Zhenhua Zhao, Jianhua Zhang, Pan Li, Yujia Cao, Xiaobo Nie, Junqing Hou","doi":"10.1186/s12967-025-07053-6","DOIUrl":"10.1186/s12967-025-07053-6","url":null,"abstract":"<p><p>Prostate cancer (PCa) remains the most prevalent malignancy among men, with the inevitable emergence of castration-resistant prostate cancer (CRPC) presenting the greatest challenge. Accumulating evidence has confirmed that the overexpression of cAMP response element-binding protein (CREB)-binding protein (CBP) and E1A-binding protein (p300), two highly homologous transcriptional coactivators, plays a crucial role in the development of PCa and its progression to CRPC, thereby making them prominent therapeutic targets for all types of PCa. In this review, we systematically discuss the structure and function of CBP/p300 and elucidate the detailed mechanisms by which CBP/p300 promote prostate carcinogenesis and development. Specifically, CBP/p300 facilitate prostate carcinogenesis by acetylating specific lysine residues on essential transcription factors involved in androgen receptor (AR) signaling, canonical Wnt signaling, p53 signaling, as well as other pathways such as PI3K/AKT and MAPK signaling. Additionally, they contribute to tumor immunosuppression and adaptive resistance to programmed death ligand 1 (PD-L1) blockade treatment by inducing the expression and secretion of the PD-L1 protein. Furthermore, we explore the latest advances in the use of various inhibitors targeting different domains of CBP/p300 and proteolysis-targeting chimeras (PROTAC) degraders in PCa. We propose that combing CBP/p300 inhibitors or degraders with current anti-PCa therapies, including androgen deprivation therapy (ADT), chemotherapy, and immunotherapy, holds potential to overcome the challenges in treating advanced PCa and improve clinical outcomes for all PCa patients.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1045"},"PeriodicalIF":7.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cathepsin K: a novel association with glucose intolerance, insulin resistance, and subclinical atherosclerosis in T2DM.","authors":"Carolina Averta, Mariangela Rubino, Elettra Mancuso, Mattia Massimino, Giuseppe Coppolino, Davide Bolignano, Velia Cassano, Marta Greco, Angela Palummo, Angela Sciacqua, Maria Perticone, Gaia Chiara Mannino, Giorgio Sesti, Francesco Andreozzi","doi":"10.1186/s12967-025-07079-w","DOIUrl":"10.1186/s12967-025-07079-w","url":null,"abstract":"<p><strong>Background: </strong>Cathepsin K (CatK) contributes to vessel collagene remodelling and high CatK concentrations have been found in atherosclerotic lesions. CatK ablation in a murine model determined an amelioration of diabetes-induced hyperglycemia and cardiovascular structural/functional abnormalities. To date, it is unknown whether glucose tolerance status affects circulating levels of CatK, and if CatK is involved with the cardiovascular complications associated with type 2 diabetes (T2DM).</p><p><strong>Methods: </strong>We assayed the levels of serum CatK in a cohort of 544 well-characterized Caucasian adults. assessing subclinical cardiovascular organ damage defined by carotid artery intima-media thickness (c-IMT) and left ventricular mass index (LVMI) in our T2DM cohort.</p><p><strong>Results: </strong>CatK levels were significantly higher in individuals with T2DM (2.3 ± 0.8 ng/ml; N = 263) compared to normoglycemia (NGT; 1.2 ± 0.5 ng/ml; N = 146) or predabetes (IFG/IGT; 1.2 ± 0.3 ng/ml; N = 135). Consistent with the literature, CatK levels correlated with age (r = - 0.190, p = 0.001), 2 h-PG (r = - 0.118, p = 0.048) and c-IMT (r = 0.157, p < 0.01) in the subset without T2DM. In the T2DM group, CatK positively correlated with FPI (r = 0.277; p < 0.001), HOMA-IR (r = 0.269; p < 0.001) and c-IMT (r = 0.155; p = 0.013). Multiple logistic regression analysis, adjusted for potential confounders, revealed that a one-quintile increment in CatK levels was associated with a 6.5-fold increased odds of T2DM. Furthermore, multiple linear regression analysis in T2DM patients, including sex, age, BMI, hypotensive therapy, and HOMA-IR (or alternatively HbA1c or FPI) as covariates, identified age and CatK as the strongest determinants of c-IMT. CatK levels did not correlate with LVMI in either the T2DM or non-T2DM cohorts.</p><p><strong>Conclusions: </strong>Our data show that the variability of CatK circulating levels is associated with glucose tolerance status, and with early signs of atherosclerosis in a population with T2DM as well as in non-diabetic individuals. These findings, combined with the established role of CatK in vascular remodeling, suggest that CatK may play a role in the early etiopathogenesis of cardiovascular complications in T2DM.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1046"},"PeriodicalIF":7.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}