Theranostics最新文献

{"title":"miR-15a-5p outperforms anti-VEGF drug in ocular neovascularization by providing dual anti-angiogenic and neuroprotective effects.","authors":"Hui Zhang, Xinyue Yu, Fuhua Yang, Rongguo Yu, Liangzhang Tan, Jinying An, Huan Wang, Yiran Cui, Wenrui Linghu, Yue Wang, Jiahui Wu, Xiaomin Zhang, Xiaorong Li","doi":"10.7150/thno.134644","DOIUrl":"10.7150/thno.134644","url":null,"abstract":"<p><strong>Background: </strong>Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders.</p><p><strong>Methods: </strong>miR-15a-5p expression levels were assessed in intraocular fluids from patients with ocular neovascular diseases. Functional assays were performed in retinal endothelial cells under pathological conditions to evaluate proliferation and endothelial-to-mesenchymal transition. <i>In vivo</i>, miR-15a-5p was delivered via intravitreal injection in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mouse models. Therapeutic effects on pathological neovascularization were analyzed and compared with anti-VEGF treatment, including assessments of retinal structural integrity, retinal function, gliosis, and fibrotic changes. miR-15a-5p-knockout mice were used to examine retinal vascular developmental abnormalities and enhanced neovascular responses following miR-15a-5p deficiency. Safety evaluations of systemic and ocular administration were performed in both healthy and neovascularized mice. Mechanistic studies investigated whether miR-15a-5p directly targeted VEGF and Smad2.</p><p><strong>Results: </strong>miR-15a-5p was significantly upregulated in intraocular fluids from patients with ocular neovascular diseases. Overexpression of miR-15a-5p inhibited retinal endothelial cell proliferation and endothelial-to-mesenchymal transition <i>in vitro</i>. In OIR and CNV models, miR-15a-5p treatment reduced retinal neovascularization, decreased reactive gliosis, and maintained retinal thickness and electrophysiological function. In miR-15a-5p-knockout mice, loss of miR-15a-5p impaired normal retinal vascular development. Mechanistically, miR-15a-5p directly targeted VEGF and Smad2, modulating angiogenic and fibrotic pathways. Compared with anti-VEGF therapy, miR-15a-5p demonstrated stronger anti-fibrotic and neuroprotective effects without affecting postnatal development or systemic metabolism. No ocular or systemic toxicity was observed at therapeutic doses.</p><p><strong>Conclusions: </strong>miR-15a-5p regulates angiogenesis and fibrosis by targeting VEGF and Smad2. These findings suggest that miR-15a-5p is a promising therapeutic candidate for the treatment of ocular neovascular diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8427-8446"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mechanobiology-driven cell-derived ECM bioink for engineering 3D glioblastoma tumor microenvironment models.","authors":"Seohyeon An, Seoyul Jo, GeunHyung Kim","doi":"10.7150/thno.137729","DOIUrl":"10.7150/thno.137729","url":null,"abstract":"<p><p>Glioblastoma (GBM) is highly aggressive and difficult to treat, partly due to the lack of <i>in vitro</i> models that faithfully recapitulate its biochemical and mechanobiological microenvironment. Synthetic hydrogels lack tumor-specific cues, while animal-derived dECM suffers from batch variability, limiting standardization.</p><p><strong>Methods: </strong>Here, we describe a GBM-derived dECM bioink formulated through mechanically stimulated 3D GBM culture within GelMA/HAMA hydrogels. By controlling the matrix stiffness to match GBM tissue and applying various compressive stresses that mimic intracranial solid stress, we identified a mechanobiological activation range that maximized secretion of GBM-associated factors, including GDF15, MMP2, and MMP9.</p><p><strong>Results: </strong>The resulting bioink exhibited upregulated tumor-specific biochemical signals compared to hydrogel-only controls. Micromesh-bioprinted GBM constructs fabricated from this bioink demonstrated enhanced proliferation, invasion-related gene expression, and ECM remodeling. Co-culture with endothelial cells or fibroblasts further reconstructed stromal activation, paracrine signaling, and matrix dynamics associated with GBM progression and therapeutic resistance.</p><p><strong>Conclusion: </strong>This strategy establishes a reproducible, bioactive GBM-specific bioink platform for physiologically relevant 3D GBM modeling and GBM-on-chip applications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8361-8384"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional nanozyme platforms in central nervous system therapies: from rational design to translational medicine.","authors":"Shufang Niu, Xiaoyin Liu, Ran Xu, An Zhu, Shihong Zhu, Fuheng Hu, Kunlun Ding, Siyi Li, Bingcan Zhu, Peize Liang, Siqi Zhang, Anqi Xiao, Kelong Fan, Zhiyong Zhang","doi":"10.7150/thno.136080","DOIUrl":"10.7150/thno.136080","url":null,"abstract":"<p><p>Central nervous system (CNS) disorders-including ischemic stroke, traumatic brain/spinal cord injury, Parkinson's disease, and Alzheimer's disease-have long faced limitations in achieving functional recovery and disease-modifying therapies because of their complex pathophysiological mechanisms. Traditional therapies are often constrained by poor penetration across CNS barriers, limited participation in multiple pathological cascades, and insufficient persistence of therapeutic effects. Nanozymes are a class of nanomaterials with enzyme-like catalytic activity and tunable physicochemical properties. Not only do these nanozymes continuously scavenge reactive oxygen and nitrogen species in pathological environments through stable multi-enzyme synergistic effects by leveraging their abundant active sites, but also serve as multimodal therapeutic delivery platforms to achieve efficient drug delivery, opening up new avenues for neuroprotection and regenerative medicine. This review systematically examines the fundamental characteristics, classification systems, and functional design approaches of nanozymes, along with their potential for combined therapeutic strategies, including synergistic applications with drugs, hydrogels, genes, or cells. Additionally, it summarizes the latest advancements in neuroprotection and repair associated with CNS disorders. The review further analyzes current limitations and challenges related to clinical translation and offers insights into future research directions to enhance scientific knowledge and clinical applications in this significant field.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8385-8426"},"PeriodicalIF":14.9,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinically accessible drug-based nano-assemblies with self-targeting ability for NIR-II fluorescence imaging-guided surgery in triple-negative breast cancer.","authors":"Ruiqin Yang, Kangliang Lou, Shuangyan Bao, Chen Yang, Yating Gai, Shuanglong Chen, Qingmo Yang, Siqi Qiu, Yilong Lin, Hairong Zhao, Yang Li","doi":"10.7150/thno.133735","DOIUrl":"10.7150/thno.133735","url":null,"abstract":"<p><strong>Rationale: </strong>Accurate intraoperative visualization is critical for reducing margin positivity during breast-conserving surgery for triple-negative breast cancer (TNBC). Second near-infrared (NIR-II) fluorescence imaging represents a promising approach for precision surgery by combining lesion detection with real-time guidance. Nevertheless, the clinical translation of most fluorescence agents remains hampered by carrier-related toxicity and complex synthesis. Therefore, a \"green\" drug-repurposing strategy was adopted here to construct carrier-free pure-drug nano-assemblies (PDNAs), aiming to provide a biocompatible and precise intraoperative navigation tool for TNBC resection.</p><p><strong>Methods: </strong>We developed a novel PDNA system (CF-ICG) formed by the simple self-assembly of two clinically employed drugs: calcium folinate and indocyanine green. The targeting specificity of CF-ICG and the feasibility of NIR-II fluorescence-guided surgery were validated using MDA-MB-231-Luc xenograft and MMTV-PyVT transgenic models. A rapid <i>ex vivo</i> incubation protocol was developed to differentiate breast cancer from para-cancer tissues.</p><p><strong>Results: </strong>Driven by intrinsic Ca²⁺ from CF, CF-ICG was assembled through π-π stacking and electrostatic interactions, demonstrating stable physicochemical properties and FRα self-targeting ability. <i>In vivo</i> imaging provided high-contrast NIR-II signals for real-time surgical navigation and enabled precise identification of residual submillimeter tumor lesions (diameter ~0.9 mm) in MDA-MB-231-Luc xenograft models. It also clearly differentiated malignant from normal breast tissues in MMTV-PyVT transgenic mice (AUC = 0.941). Furthermore, the diagnostic performance of the rapid <i>ex vivo</i> incubation protocol was preliminarily validated using surgical specimens from TNBC patients (n = 11). Notably, this approach effectively differentiated tumors from para-cancer tissues within 12 min (AUC = 0.926).</p><p><strong>Conclusions: </strong>By combining a \"green\" fabrication process with a drug-repurposing strategy, we developed CF-ICG as a carrier-free PDNA with tumor self-targeting capability, enabling precise intraoperative navigation in preclinical models and <i>ex vivo</i> tissues. These findings support the further development of this approach for more accurate tumor visualization and surgical decision-making in TNBC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8284-8301"},"PeriodicalIF":14.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnetofection-mediated siRNA delivery ameliorates cartilage damage in Kashin-Beck disease <i>via</i> targeting SIRT3 and protecting primary cilia.","authors":"Yangmengfan Chen, Duan Wang, Yao Zhang, Xiaoyang Liu, Ze Du, Xuming Chen, Xufeng Wan, Yongrui Cai, Anjing Chen, Jiehao Chen, Hao Du, Zongke Zhou","doi":"10.7150/thno.134335","DOIUrl":"10.7150/thno.134335","url":null,"abstract":"<p><strong>Rationale: </strong>Kashin-Beck disease (KBD) is an endemic osteochondropathy caused by T-2 toxin, however, the molecular mechanism underlying T-2 toxin-induced chondrocyte damage remains unclear. This study aimed to elucidate the pathogenic role of T-2 toxin in KBD and develop an EMF-augmented nanotherapy for KBD-related cartilage damage.</p><p><strong>Methods: </strong>This study investigated T-2 toxin-induced chondrocyte damage by evaluating protein acetylation, primary cilia integrity and the levels of chondrogenic markers (Sox9, Col2a1). <i>In vitro</i> experiments were performed via pharmacological and genetic SIRT3 inhibition. To protect chondrocytes, si-<i>SIRT3</i>@SPIONs were fabricated, and EMF was applied to improve cell transfection and silencing efficiency. A KBD model in SD rats was used to validate the <i>in vivo</i> therapeutic effect; immunohistochemical staining and micro-CT scanning and reconstruction were performed to comprehensively evaluate <i>in vivo</i> treatment efficacy.</p><p><strong>Results: </strong>Pathological <i>SIRT3</i> overexpression induced by T-2 toxin disrupted chondrocyte protein acetylation, impaired primary cilia integrity, and suppressed the gene expression of chondrogenic markers. <i>SIRT3</i> inhibition efficiently protected T-2 toxin-induced chondrocyte cytotoxicity <i>in vitro</i>. Furthermore, EMF-augmented si-<i>SIRT3</i>@SPIONs treatment ameliorated cartilage damage, preserved matrix composition and restored normal chondrocyte phenotype in KBD model rats.</p><p><strong>Conclusions: </strong>T-2 toxin induces chondrocyte injury and promotes KBD progression mainly by disrupting primary cilia integrity and protein acetylation, with <i>SIRT3</i> overexpression acting as a mediating factor. The EMF-augmented si-<i>SIRT3</i>@SPIONs therapy can effectively protect T-2 toxin-induced primary cilia damage and cartilage degeneration, thus providing a promising therapeutic modality for KBD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8302-8325"},"PeriodicalIF":14.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic-Immune Reprogramming via CuZnS@BSA Nanoregulators to Overcome Resistance in Triple-Negative Breast Cancer.","authors":"Jingyi Yang, Qi Li, Pi Zhao, Zixin Luo, Zhaokai Wang, Rui Yang, Min Zhou, Jie Zhou, Daozhen Chen, Yu Chen","doi":"10.7150/thno.134131","DOIUrl":"10.7150/thno.134131","url":null,"abstract":"<p><strong>Rationale: </strong>Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its 'cold' immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered 'disarm-and-attack' cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment.</p><p><strong>Methods: </strong>Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated <i>in vitro</i> using 4T1 cells. <i>In vivo</i> anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade.</p><p><strong>Results: </strong>The platform first releases H₂S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu²⁺ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn²⁺ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and <i>in vivo</i> experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8⁺ T cell infiltration and enhanced dendritic cell maturation.</p><p><strong>Conclusion: </strong>Combining this nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8263-8283"},"PeriodicalIF":14.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR2 deficiency protects against doxorubicin-induced cardiac dysfunction through enhanced IL12B-dependent autophagy.","authors":"Lizhi Hu, Li Lin, Long Chen, Yuhang Wang, Lulu Ning, Wanheng Tu, Cheng Wang, Shan Deng, Kai Huang","doi":"10.7150/thno.131005","DOIUrl":"10.7150/thno.131005","url":null,"abstract":"<p><strong>Rationale: </strong>Doxorubicin (DOX) is a potent chemotherapeutic agent whose antitumor benefits are limited by a well-recognized, dose-dependent cardiotoxicity. While previous studies have implicated inflammatory pathways in DOX-induced cardiomyopathy (DIC), the role of CCR2 in this process remains incompletely defined. This study aims to investigate whether CCR2 deficiency confers cardioprotection against DIC and to uncover the molecular mechanisms involved.</p><p><strong>Methods: </strong>CCR2 knockout (<i>CCR2^⁻/⁻</i> ) mouse was subjected to both acute and chronic DIC models. Bone marrow transplantation was used to establish the functional contribution of CCR2-deficient macrophages. Autophagic flux was evaluated using complementary approaches, including a tandem mRFP-GFP-LC3 reporter, western blotting, immunofluorescence, and transmission electron microscopy. The mediator linking CCR2-deficient macrophages to cardiomyocytes was identified by proteomics and validated using recombinant IL12B protein and a neutralizing antibody.</p><p><strong>Results: </strong>CCR2 deficiency substantially improved cardiac function, as evidenced by preserved left ventricular ejection fraction, fractional shortening and reduced serum cardiac injury markers. Mechanistic studies revealed that <i>CCR2^⁻/⁻</i> hearts exhibited enhanced autophagic flux, with increased LC3B lipidation, autophagosome formation, and clearance of damaged cellular components. Proteomic profiling of cardiac macrophages identified interleukin-12B (IL12B) significantly upregulated in <i>CCR2^⁻/⁻</i> mouse. Recombinant IL12B protein administration activated cardiomyocyte autophagy through PI3K/Akt/mTOR pathway inhibition and reproduced the cardioprotective effects in WT mouse. Conversely, IL12B neutralization completely abolished CCR2 deficiency-mediated protection.</p><p><strong>Conclusions: </strong>Our findings identify a novel CCR2-IL12B-autophagy axis that critically regulates DOX-induced cardiotoxicity. CCR2 deficiency promotes IL12B secretion from cardiac macrophages, which directly activates protective autophagy in cardiomyocytes. These results establish CCR2 inhibition and IL12B supplementation as two promising therapeutic strategies to prevent chemotherapy-induced cardiomyopathy, providing a transformative approach to cardio-oncology.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8326-8346"},"PeriodicalIF":14.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reshaping immune cell distribution with mRNA noncationic lipid nanoparticles for overcoming neoadjuvant chemo-immunotherapy resistance.","authors":"Yiwen Liu, Rui Chang, Kenan Chen, Lin Li, Xiaogang An, Shegan Gao, Dingjun Zha, Hongzhang Deng","doi":"10.7150/thno.136879","DOIUrl":"10.7150/thno.136879","url":null,"abstract":"<p><strong>Rationale: </strong>Fusobacterium nucleatum (Fn) is associated with resistance to neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma (ESCC), but the underlying mechanism is unclear. We identified Fn-induced SPP1⁺ macrophages as key drivers of a cancer-associated fibroblast (CAF)-mediated spatial immune barrier that restricts CD8⁺ T-cell infiltration.</p><p><strong>Methods: </strong>Mannose-modified non-cationic thiourea lipid nanoparticles (NC-TNP^M) were engineered to deliver Cas9 mRNA and SPP1-targeting sgRNA to macrophages. Their therapeutic efficacy was evaluated in Fn-associated ESCC models combined with chemotherapy and anti-PD-L1 treatment.</p><p><strong>Results: </strong>NC-TNP^M achieved efficient SPP1 silencing, markedly reduced SPP1⁺ macrophages, disrupted the macrophage-CAF immune barrier, and restored intratumoral CD8⁺ T-cell infiltration. Combined with chemo-immunotherapy, NC-TNP^M significantly suppressed tumor growth, enhanced cytotoxic T-cell activity, promoted macrophage repolarization, and showed no evident toxicity.</p><p><strong>Conclusions: </strong>Fn-induced SPP1⁺ macrophages drive immune exclusion and chemo-immunotherapy resistance in ESCC. Macrophage-targeted SPP1 editing with NC-TNP^M overcomes this barrier and enhances therapeutic efficacy, highlighting a promising nanomedicine strategy for ESCC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8347-8360"},"PeriodicalIF":14.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTPS1 is an unexplored vulnerability in breast and ovarian cancer.","authors":"Xiyin Wang, Michael J Emch, Lauren A Voll, Rebecca Epp, Esther P B Rodman, Noa J Odell, Hannah M Smith, Nicole A Pearson, Xiaonan Hou, Ya Li, Melissa C Larson, Ann L Oberg, Taro Hitosugi, Matthew P Goetz, Scott H Kaufmann, S John Weroha, Philip A Beer, John R Hawse","doi":"10.7150/thno.134720","DOIUrl":"10.7150/thno.134720","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches.</p><p><strong>Methods: </strong>Using the DepMap database, we first sought to identify genes that were highly expressed and more essential for proliferation/viability in TNBC cells relative to other breast cancer subtypes. Candidate genes were validated using gene-specific siRNAs in a panel of TNBC and estrogen receptor positive breast cancer cells. CTPS1 expression, and its functional significance, was further evaluated in ovarian cancer models, including chemotherapy- and PARP inhibitor-resistant cell lines. Pharmacologic inhibition was assessed using STP938, a first-in-class selective CTPS1 inhibitor, in TNBC and ovarian cancer cells as well as in <i>ex vivo</i> and <i>in vivo</i> patient-derived xenografts (PDX).</p><p><strong>Results: </strong>Six genes (CTPS1, HUS1, PRKRA, RAD1, RAD9A, and RHOA) were identified as potential TNBC selective dependencies. Among these, CTPS1 was prioritized for further study given that it was highly expressed, further upregulated in chemotherapy- and PARP inhibitor-resistant cell lines, and resulted in the greatest anti-neoplastic effects when depleted. Knockdown of CTPS1 confirmed its selective essentiality and resulted in rapid and durable S-phase cell cycle arrest. Pharmacologic inhibition of CTPS1 with STP938 led to robust anti-neoplastic effects at nM concentrations across both chemotherapy-sensitive and -resistant TNBC and ovarian cancer cell lines. Significant anti-neoplastic activity was observed in 6 independent <i>ex vivo</i> ovarian cancer PDX models. Further, STP938 significantly inhibited progression of an ovarian cancer PDX model <i>in vivo</i>.</p><p><strong>Conclusion: </strong>These findings identify CTPS1 as a critical dependency in TNBC and ovarian cancer. Selective pharmacologic inhibition of CTPS1 using STP938 is a potent inhibitor of tumor cell proliferation/viability and has anti-cancer activity in patient derived <i>ex vivo</i> and <i>in vivo</i> tumor models. These findings suggest that therapeutic targeting of CTPS1 represents an alternative approach for the management of patients with advanced and aggressive forms of these diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8195-8214"},"PeriodicalIF":14.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MENTSH: A novel mitochondrial microprotein linked to a SNP associated with type 2 diabetes.","authors":"Kelvin Yen, Ricardo Ramirez, Brendan Miller, Hiroshi Kumagai, Jie Yao, Morgan Levine, Xiuqing Guo, Jihui Sha, Ana Silverstein, Roberto Vicinanza, Kent D Taylor, Melanie Flores, Zeferino Reyna, Su-Jeong Kim, Noel Guerrero, Hemal H Mehta, Junxiang Wan, Zhongzheng Niu, Carrie V Breton, Maria C Kenney, Thalida Em Arpawong, James Wohlschlegel, Jerome I Rotter, Eileen Crimmins, Pinchas Cohen","doi":"10.7150/thno.134637","DOIUrl":"10.7150/thno.134637","url":null,"abstract":"<p><strong>Rationale: </strong>Obesity and type 2 diabetes (T2D) are growing threats to human health, and their genetic basis is complex and not fully understood. Furthermore, the mitochondrial genome has been shown to encode for many microproteins that have a variety of biological effects. In this study we explore a newly discovered <b>m</b>itochondrial-<b>d</b>erived micro<b>p</b>rotein (MDP) that may be responsible for some forms of diabetes in humans.</p><p><strong>Methods: </strong>We have performed a mitochondrial genome wide interaction study (MiWIS) and discovered a SNP that lies within the gene for an MDP and is associated with type 2 diabetes. We then used cell culture to confirm that this MDP has biological activity and used mass spectrometry to detect it. This novel MDP and more potent analogues were then administered in murine, <i>in vivo</i> studies in models of diabetes and obesity to determine the effects. Further analysis of the <i>in vivo</i> studies was performed with transcriptomic and proteomic techniques.</p><p><strong>Results: </strong>Our MiWIS found a SNP associated with type 2 diabetes in 3 independent cohorts that is found within a novel MDP that we have called MENTSH (<b>M</b>DP <b>E</b>ncoded in the <b>N</b>D-<b>T</b>wo <b>S</b>ubunit of <b>H</b>umans). This common SNP is found in populations indigenous to the Americas that interrupts the start codon of MENTSH. Murine <i>in vivo</i> studies demonstrate that MENTSH administration improves insulin signaling, while analogues of MENTSH can potently block weight gain caused by a high fat diet. Mechanistically, our studies show that MENTSH activates AKT signaling in muscle, while reducing AKT signaling in fat.</p><p><strong>Conclusions: </strong>These observations highlight a new cause of metabolic dysfunction in a vulnerable population, suggesting that MENTSH could be an innovative, precision medicine approach to treating T2D.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 14","pages":"8180-8194"},"PeriodicalIF":14.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}