Journal of Translational Medicine最新文献

{"title":"Machine learning models for predicting metabolic dysfunction-associated steatotic liver disease prevalence using basic demographic and clinical characteristics.","authors":"Gangfeng Zhu, Yipeng Song, Zenghong Lu, Qiang Yi, Rui Xu, Yi Xie, Shi Geng, Na Yang, Liangjian Zheng, Xiaofei Feng, Rui Zhu, Xiangcai Wang, Li Huang, Yi Xiang","doi":"10.1186/s12967-025-06387-5","DOIUrl":"https://doi.org/10.1186/s12967-025-06387-5","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern that necessitates early screening and timely intervention to improve prognosis. The current diagnostic protocols for MASLD involve complex procedures in specialised medical centres. This study aimed to explore the feasibility of utilising machine learning models to accurately screen for MASLD in large populations based on a combination of essential demographic and clinical characteristics.</p><p><strong>Methods: </strong>A total of 10,007 outpatients who underwent transient elastography at the First Affiliated Hospital of Gannan Medical University were enrolled to form a derivation cohort. Using eight demographic and clinical characteristics (age, educational level, height, weight, waist and hip circumference, and history of hypertension and diabetes), we built predictive models for MASLD (classified as none or mild: controlled attenuation parameter (CAP) ≤ 269 dB/m; moderate: 269-296 dB/m; severe: CAP > 296 dB/m) employing 10 machine learning algorithms: logistic regression (LR), multilayer perceptron (MLP), extreme gradient boosting (XGBoost), bootstrap aggregating, decision tree, K-nearest neighbours, light gradient boosting machine, naive Bayes, random forest, and support vector machine. These models were externally validated using the National Health and Nutrition Examination Survey (NHANES) 2017-2023 datasets.</p><p><strong>Results: </strong>In the hospital outpatient cohort, machine learning algorithms demonstrated robust predictive capabilities. Notably, LR achieved the highest accuracy (ACC) of 0.711 in the test cohort and 0.728 in the validation cohort, coupled with robust areas under the receiver operating characteristic curve (AUC) values of 0.798 and 0.806, respectively. Similarly, MLP and XGBoost showed promising results, with MLP achieving an ACC of 0.735 in the test cohort, and XGBoost registering an AUC of 0.798. External validation using the NHANES datasets yielded consistent AUC results, with LR (0.831), MLP (0.823), and XGBoost (0.784) performing robustly.</p><p><strong>Conclusions: </strong>This study demonstrated that machine learning models constructed using a combination of essential demographic and clinical characteristics can accurately screen for MASLD in the general population. This approach significantly enhances the feasibility, accessibility, and compliance of MASLD screening and provides an effective tool for large-scale health assessments and early intervention strategies.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"381"},"PeriodicalIF":6.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742921","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":"Quadrant asymmetry alteration of deep retinal capillary plexus degeneration in pathological myopia.","authors":"Yilei Shao, Meixiao Shen, Fan Lu, Jie Ye","doi":"10.1186/s12967-025-06385-7","DOIUrl":"https://doi.org/10.1186/s12967-025-06385-7","url":null,"abstract":"<p><strong>Background: </strong>To measure quadrant asymmetry (QA) alterations of macular retinal microvascular density and determine their effect on pathological myopia.</p><p><strong>Methods: </strong>Optical coherence tomography angiography (OCTA) images of 20 control, 42 simple high myopia and 20 pathological myopia eyes were analyzed to quantify the density of the macular retinal microvascular network that included the superficial and deep retinal capillary plexuses (SRCP and DRCP). The definition of QA was calculated by subtracting the minimum value from the maximum value among the four macular respective subfields. The comparison of the QAs of SRCP and DRCP density among the three groups and the effect of QAs on the occurrence of pathological myopia were analyzed.</p><p><strong>Results: </strong>In pathological myopia, densities of the SRCP and DRCP were lower than in simple high myopia and control (P < 0.05). The higher QAs of SRCP and DRCP density occurred in pathological myopia than in simple high myopia and control (P < 0.05). In multivariate binary logistic regression, higher QA of DRCP density was associated significantly with the occurrence of pathological myopia (Odds Ratio = 2.000, P = 0.035) while the QA of SRCP density didn't (P = 0.065). Comparing the intra-quadrant effect on the occurrence of pathological myopia with the analysis of binary multivariate logistic regression, the decreased DRCP density in the macular inferior subfield showed a high risk (Odds Ratio = 0.435, P = 0.030).</p><p><strong>Conclusions: </strong>The occurrence of pathological myopia affected the quadrant asymmetry alterations of macular retinal microvascular density, especially the increased QA of DRCP density with significantly decreased DRCP density in the macular inferior subfield.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"378"},"PeriodicalIF":6.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743029","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":"Circ-ITCH promotes the ubiquitination degradation of HOXC10 to facilitate osteogenic differentiation in disuse osteoporosis through stabilizing BRCA1 mRNA via IGF2BP2-mediated m⁶A modification.","authors":"Da Zhong, Xi Li, Zhen Yin, Peng Chen, Yusheng Li, Jian Tian, Long Wang, Hua Liu, Ke Yin, Lemei Zhu, Lingyu Kong, Kunli Chen, Yaochun Li, Chungu Hong, Chenggong Wang","doi":"10.1186/s12967-024-06050-5","DOIUrl":"10.1186/s12967-024-06050-5","url":null,"abstract":"<p><strong>Background: </strong>Osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) facilitated by mechanical loading is a promising therapy for disuse osteoporosis (DOP), however, it is difficult to implement mechanical loading for a majority of patients. Our study aims to identify circ-ITCH-mediated novel approach to facilitate osteogenic differentiation in DOP.</p><p><strong>Methods: </strong>A rat DOP model and human BM-MSCs under microgravity condition were generated as in vivo and in vitro models of DOP, respectively. The bone mineral density (BMD) and bone parameters were examined in rats. The histological changes of bones and mineralization were monitored by H&E, Alcian blue and Alizarin red S staining. Co-IP was employed to examine the ubiquitination of HOXC10 and the interaction between HOXC10 and BRCA1. The direct associations among circ-ITCH, IGFBP2 and BRCA1 mRNA were assessed by RIP, FISH and RNA pull-down assays.</p><p><strong>Results: </strong>Circ-ITCH was downregulated in rat model of DOP and BM-MSCs under microgravity stimulation. Circ-ITCH overexpression promoted osteogenic differentiation in BM-MSCs under microgravity condition. The altered bone parameters, such as BMD, trabecular number (Tb.N), trabecular separation (Tb.Sp), trabecular thickness (Tb.Th), and bone microstructure in DOP rats were rescued by circ-ITCH overexpression. Mechanistically, circ-ITCH enhanced the ubiquitination degradation of HOXC10 through enhancing BRCA1 mRNA stability. Circ-ITCH directly bound to IGF2BP2 protein to stabilize BRCA1 mRNA via m⁶A modification, thus facilitating osteogenic differentiation in BM-MSCs under microgravity condition.</p><p><strong>Conclusion: </strong>Circ-ITCH stabilized BRCA1 mRNA via IGF2BP2-mediated m⁶A modification, thereby facilitating the ubiquitination degradation of HOXC10 to promote osteogenic differentiation in DOP.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"376"},"PeriodicalIF":6.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730357","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":"The mechanisms and applications of endothelial progenitor cell therapy in the treatment of intracranial aneurysm.","authors":"Shiyu Shen, Tonglin Pan, Peixi Liu, Yanlong Tian, Yuan Shi, Wei Zhu","doi":"10.1186/s12967-025-06401-w","DOIUrl":"10.1186/s12967-025-06401-w","url":null,"abstract":"<p><p>The pathophysiological mechanism of intracranial aneurysm (IA) involves the dynamic interaction of ECM abnormalities, hemodynamic stress, and inflammatory response. The rupture of intracranial aneurysm will cause serious consequences. Multiple studies have confirmed the important role and potential application of endothelial progenitor cells (EPCs) in vascular repair. This review focuses on the specific mechanism of EPCs in the treatment of intracranial aneurysms, which promote re-endothelialization and angiogenesis through bone marrow mobilization, targeted migration to the site of injury, differentiation into mature endothelial cells, and secretion of angiogenic factors. In addition, EPCs maintain ECM homeostasis by regulating MMP/IMP balance, inhibiting aneurysm wall thinning and structural damage. Based on the vascular repair mechanism of EPCs, new treatment strategies such as \"biologically active\" spring coils (loaded with EPCs or SDF-1α) and flow diverters(FDs) combined with EPCs therapy have been developed to synergistically promote carotid endothelialization of aneurysms and reduce the risk of recurrence. Future research needs to further validate the long-term efficacy and precise regulatory mechanisms of EPCs in clinical translation, providing new directions for IA treatment.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"377"},"PeriodicalIF":6.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730273","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":"Spatial relationships and interactions of immune cell niches are linked to the pathologic response of muscle-invasive bladder cancer to neoadjuvant therapy.","authors":"Wasilijiang Wahafu, Quan Zhou, Xihua Yang, Yongming Yang, Yuanyuan Zhao, Zhu Wang, Xiangpeng Kang, Xiongjun Ye, Nianzeng Xing","doi":"10.1186/s12967-025-06358-w","DOIUrl":"10.1186/s12967-025-06358-w","url":null,"abstract":"<p><strong>Background: </strong>The identification of the complex spatial architecture of immune cell infiltration and its interaction mechanisms within tumor ecosystems provides crucial insights into therapeutic responses to neoadjuvant therapy in muscle-invasive bladder cancer (MIBC). This study aims to characterize the spatial features of distinct cell-type niches within the tumor microenvironment (TME) of patients with varying responses to neoadjuvant therapy.</p><p><strong>Methods: </strong>We performed spatial transcriptomic profiling on six MIBC specimens obtained from a registered clinical trial (ChiCTR2000032359), generating whole-transcriptome spatial atlases to map the TME architecture. High-throughput analytical frameworks were employed to deconstruct the TME, and key findings were validated through immunohistochemistry and mouse model experiments.</p><p><strong>Results: </strong>Our analysis revealed that tissues from complete responders exhibited greater infiltration of T and B cells, with the formation of tertiary lymphoid structure (TLS). Trajectory analysis identified CCL19/CCL21 as the key signaling molecules driving TLS formation in MIBC. Mouse experiments demonstrated that recombinant CCL19/CCL21 protein injections promoted intratumoral TLS formation and enhance the efficacy of immunotherapy. Furthermore, we observed significant intrinsic heterogeneity within individual tumors, which may contribute to the lack of therapeutic efficacy in MIBC.</p><p><strong>Conclusions: </strong>This study underscores the critical role of TLS formation in the response to neoadjuvant therapy in MIBC. We identified CCL19/CCL21 as key drivers of TLS formation within MIBC tumors and potential immune-sensitizing agents. Additionally, the intrinsic heterogeneity of tumor should be considered a significant factor influencing therapeutic efficacy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"375"},"PeriodicalIF":6.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730358","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":"Combined analysis of single-cell and bulk transcriptome sequencing data identifies critical glycolysis genes in idiopathic pulmonary arterial hypertension.","authors":"Xuan Gao, Youli Fan, Guijia Wang, Jiangjiang Xu, Runwei Deng, Jiangwei Song, Binfeng Sun, Yongbing Wang, Zixuan Wu, Ruyi Jia, Jing Huang, Huiyu He, Lei Gao, Yihao Zhang, Na Sun, Bingxiang Wu","doi":"10.1186/s12967-025-06373-x","DOIUrl":"10.1186/s12967-025-06373-x","url":null,"abstract":"<p><strong>Background: </strong>Abnormal glycolytic metabolism plays a significant role in pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH), yet the specific mechanisms remain unclear. The primary objective of this study is to investigate the key regulatory mechanisms of glycolysis in IPAH.</p><p><strong>Methods: </strong>Bulk and single-cell sequencing data obtained from IPAH patient tissue samples were downloaded from the GEO database. scMetabolism and AUCcell analyses of the IPAH single-cell sequencing data were carried out to quantify the glycolytic metabolic activity and identify the main cell types regulating glycolysis, respectively. The ssGSEA method was used to assess the glycolytic activity in each bulk sample within the bulk sequencing data. Differential analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were conducted to identify key genes associated with glycolysis in IPAH samples. Single-cell sequencing and a monocrotaline (MCT)-induced model of PH in rats were utilized to validate the expression of these key genes.</p><p><strong>Results: </strong>Single-cell sequencing data indicated that IPAH patients displayed increased glycolytic activity, which was primarily regulated by fibroblasts. Similarly, bulk transcriptomic data revealed a significant increase in glycolytic activity in IPAH patients. Differential analysis, WGCNA, PPI network analysis, and integrated single-cell analysis further identified insulin-like growth factor-1 (IGF1), lysyl-tRNA synthetase (KARS), caspase-3 (CASP3), and cyclin-dependent kinase inhibitor 2 A (CDKN2A) as key genes associated with fibroblast-mediated glycolysis in IPAH patients. Differential expression of IGF1, KARS, CASP3, and CDKN2A was also observed in our in vivo model of PH.</p><p><strong>Conclusion: </strong>Our study identifies IGF1, KARS, CASP3, and CDKN2A as key regulatory genes in glycolysis in IPAH, which provides the basis for the development of targeted therapies.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"373"},"PeriodicalIF":6.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719935","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":"Leveraging AAV1-Rac1T17N to prevent experimental proliferative vitreoretinopathy.","authors":"Duo Li, Minli Linghu, Jisen Tang, Gukun Yang, Chuanwu Li, Hang Yao, Hetian Lei, Yikeng Huang, Xionggao Huang","doi":"10.1186/s12967-025-06391-9","DOIUrl":"10.1186/s12967-025-06391-9","url":null,"abstract":"<p><strong>Background: </strong>Platelet-derived growth factor receptor β (PDGFRβ) is the principal PDGFR isoform in retinal pigment epithelial (RPE) cells from the epiretinal membranes of patients with proliferative vitreoretinopathy (PVR). Ras-related C3 Botulinum toxin substrate 1 (Rac1), a member of the Rho family, is a crucial factor in the cell migration and contraction processes that are inherent to the pathogenesis of PVR. The mutants Rac1T17N and Rac1Q61L can block and promote Rac1 activation, respectively. The major objective of this research was to ascertain whether PDGFRβ mediates vitreous-induced Rac1 activation and whether Rac1T17N could be leveraged for the prevention of PVR pathogenesis in a rabbit model.</p><p><strong>Methods: </strong>A pull-down assay was used to examine GTP Rac1 levels, which are indicative of Rac1 activation, and western blotting was used to assess cellular protein expression. A CCK8 assay, a wound healing assay, a transwell invasion assay and a collagen contraction assay were employed to analyze cell proliferation, migration, invasion and contraction capacity, respectively. A PVR model was created by injecting platelet-rich plasma and human retinal pigment epithelial cells (ARPE-19) into the vitreous cavities of rabbits, and this model was used to evaluate the severity of PVR impacted by intravitreally injected ARPE-19 cells transduced with adeno-associated virus (AAV)1-Rac1T17N or Rac1Q61L. PVR grade was evaluated by a double-blinded investigator according to the Fastenberg classification; in addition, ultrasound and histological analyses were performed to assess PVR severity.</p><p><strong>Results: </strong>Vitreous-induced GTP Rac1 is mediated by PDGFRβ. There was a significant decrease in vitreous-induced GTP Rac1 in ARPE-19 cells transduced with AAV1-Rac1T17N compared with those transduced with AAV1-GFP. In addition, the suppression of GTP Rac1 production in human RPE cells by transduction with AAV1-Rac1T17N inhibited vitreous-induced proliferation, migration, invasion, and contractility. Importantly, the results of the animal experiments indicated that although there was a significant increase in PVR potential in rabbits intravitreally injected with ARPE-19 cells infected with AAV1-Rac1Q61L, there was a significant decrease in PVR potential in rabbits intravitreally injected with ARPE-19 cells infected with AAV1-Rac1T17N (P < 0.01).</p><p><strong>Conclusions: </strong>AAV1-Rac1T17N has great potential for PVR therapy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"374"},"PeriodicalIF":6.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719938","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":"Peptide hydrogel platform encapsulating manganese ions and high-density lipoprotein nanoparticle-mimicking nanovaccines for the prevention and treatment of gastric cancer.","authors":"Xu Huang, Lin Hong, Yufan Lv, Kejun Li, Zengxing Zhang, Junjian Deng, Lei Shen","doi":"10.1186/s12967-025-06088-z","DOIUrl":"10.1186/s12967-025-06088-z","url":null,"abstract":"<p><strong>Background: </strong>Advanced gastric cancer remains a significant global health challenge, with limited therapeutic options available. In contrast, immunotherapy have emerged as promising alternatives, offering greater potency in treating advanced gastric cancer. However, the development of novel and efficient immunotherapeutic strategy is crucial to enhance the body's immune response against gastric cancer.</p><p><strong>Methods: </strong>This study developed a single-injection peptide hydrogel-based nanovaccine therapy for gastric cancer treatment. The therapy utilizes a RADA₃₂ peptide hydrogel, which is sensitive to metal ion concentration, to encapsulate manganese ions and HPPS nanovaccines. The HPPS nanovaccines contain antigen peptide and CpG-ODN, designed to activate both the toll-like receptor 9 (TLR9) and cGAS-STING signaling pathways in antigen-presenting cells. This design aims to facilitate a stable and sustained release of the nanovaccine, thereby enhancing the body's effective recognition and response to antigens.</p><p><strong>Results: </strong>The efficacy of the system was confirmed using the model antigen OVA and the gastric cancer-specific antigen MG7-related peptide. The results demonstrated that the nanovaccine effectively activated the immune response, leading to enhanced recognition and response to the antigens. This activation of both TLR9 and cGAS-STING pathways in antigen-presenting cells was crucial for the observed immune response, highlighting the potential of this approach to stimulate a robust and sustained immune response against gastric cancer.</p><p><strong>Conclusions: </strong>This study presents a novel strategy for clinical anti-tumor vaccine administration, offering a promising approach for the prevention and treatment of gastric cancer. The single-injection peptide hydrogel-based nanovaccine system provides a convenient and effective method to enhance the body's immune response against gastric cancer. This approach could potentially be expanded to other types of cancer, providing a versatile platform for cancer immunotherapy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"371"},"PeriodicalIF":6.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710379","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":"Colorectal cancer cells-derived exosomal miR-188-3p promotes liver metastasis by creating a pre-metastatic niche via activation of hepatic stellate cells.","authors":"Tao Li, Taiyuan Li, Yahang Liang, Yuli Yuan, Yang Liu, Yao Yao, Xiong Lei","doi":"10.1186/s12967-025-06334-4","DOIUrl":"10.1186/s12967-025-06334-4","url":null,"abstract":"<p><strong>Background/aim: </strong>Metastasis is the leading cause of mortality for colorectal cancer (CRC). Cancer-derived exosomes are widely recognized as the primary catalysts behind the development of pre-metastasis niche (PMN) in distal sites. However, the exact mechanism behind this process in CRC remains elusive. This study aimed to investigate the function and mechanisms underlying the role of exosomal miR-188-3p in activating hepatic stellate cells (HSCs) to develop the PMN and promote liver metastasis.</p><p><strong>Methods: </strong>We extracted exosomes from CRC cells using ultracentrifugation. Exosomes were identified using transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Exosome uptake was assessed using fluorescence tracing, exosome PKH67 staining, and real-time quantitative PCR. The effects of CRC cell-derived exosomes on HSCs migration were evaluated using Transwell migration and wound healing assays. Key differentially expressed miRNAs were screened from the GEO database, and bioinformatics prediction along with dual-luciferase reporter assays were used to identify downstream target genes of miR-188-3p. Downstream related proteins of the target genes were detected by Western blot. In vivo, the distribution of exosomes and activation of HSCs in the liver were explored by tail vein injection of exosomes into nude mice. Further, the impact of exosomal miR-188-3p on liver metastasis was investigated using a spleen injection liver metastasis model. Finally, the expression levels of miR-188-3p in exosomes from CRC patient plasma were determined by real-time quantitative PCR, and the relationship between the expression of miR-188-3p in plasma exosomes and CRC prognosis was analyzed.</p><p><strong>Results: </strong>The expression level of miR-188-3p within plasma exosomes demonstrated a statistically significant increase in CRC with liver metastasis compared to those without liver metastases. We also demonstrated the transferability of miR-188-3p from CRC cells to HSCs cells via the exosomes. Exosomal miR-188-3p plays a pivotal role in orchestrating the establishment of PMN through targeting PHLPP2 to activate HSCs before tumor metastasis. Exosomal miR-188-3p was found to actively foster in vivo metastasis of CRC. Additionally, plasma exosomal miR-188-3p potentially serves as a viable blood-based biomarker for CRLM.</p><p><strong>Conclusion: </strong>Exosomal miR-188-3p derived from CRC cells can promote liver metastasis by activating HSCs to form a PMN through targeting PHLPP2 to activate the AKT/mTOR pathway. These results offer a new perspective on the mechanisms driving CRLM.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"369"},"PeriodicalIF":6.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710375","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":"LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.","authors":"Qiqi Xue, Wenxi Wang, Jie Liu, Dachi Wang, Tianyu Zhang, Tingting Shen, Xiangsheng Liu, Xiaojia Wang, Xiying Shao, Wei Zhou, Xiaohong Fang","doi":"10.1186/s12967-024-05946-6","DOIUrl":"10.1186/s12967-024-05946-6","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.</p><p><strong>Methods: </strong>Immunohistochemistry and sequencing data reanalysis were used to investigate LRPPRC expression in TNBC. In vitro and in vivo assays were applied to investigate the roles of LRPPRC in TNBC progression. RT-qPCR, immunoblotting, and Seahorse XF assay were used to examine LRPPRC's functions in the expression of OXPHOS subunits and energy metabolism. In vitro and in vivo functional assays were used to test the therapeutic effect of gossypol acetate (GAA), a traditional gynecological drug, on LRPPRC suppression and OXPOHS inhibition.</p><p><strong>Results: </strong>LRPPRC was specifically overexpressed in TNBC. LRPPRC knockdown suppressed the proliferation, metastasis, and tumor formation of TNBC cells. LRPPRC enhanced OXPHOS metabolism by increasing the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA inhibited OXPHOS metabolism by directly binding LRPPRC, causing LRPPRC degradation, and downregulating the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA administration suppressed TNBC cell proliferation, metastasis in vitro, and tumor formation in vivo.</p><p><strong>Conclusions: </strong>This work demonstrated a new regulatory pathway of TNBC to promote the expression of mitochondrial genes by upregulating the nuclear gene LRPPRC, resulting in increased OXPHOS. We also suggested a promising therapeutic target LRPPRC for TNBC, and its inhibitor, the traditional gynecological medicine GAA, presented significant antitumor activity.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"372"},"PeriodicalIF":6.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710377","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}