Theranostics最新文献

{"title":"Gut microbiota depletion accelerates hematoma resolution and neurological recovery after intracerebral hemorrhage via p-coumaric acid-promoted Treg differentiation.","authors":"Yonghe Zheng, Yin Li, Xuchao He, Yuhan Zhu, Shiyu Xu, Yirong Feng, Yirui Kuang, Huaijun Chen, Linfeng Fan, Huaping Huang, Libin Hu, Xian Yu, Jianan Wu, Lingji Jin, Junwen Hu, Xiongjie Fu, Hanhai Zeng, Shenglong Cao, Lin Wang","doi":"10.7150/thno.113764","DOIUrl":"10.7150/thno.113764","url":null,"abstract":"<p><p>Hematoma volume significantly influences the prognosis of patients with intracerebral hemorrhage (ICH). Effective resolution of hematoma through enhanced clearance mechanisms and reduced hematoma lysis is essential for neurological recovery following ICH. Regulatory T cells (Tregs), known for their anti-inflammatory properties, exert neuroprotective effects in various central nervous system disorders. Additionally, gut microbiota profoundly impacts Treg development through multiple regulatory pathways. Nonetheless, the precise roles of Tregs and gut microbiota in facilitating hematoma resolution after ICH remain unclear. This study, therefore, aimed to investigate the contributions of Tregs and gut microbiota to hematoma resolution post-ICH, as well as the underlying mechanisms. <b>Methods:</b> The impact of gut microbiota depletion on neurological deficits and hematoma resolution, including erythrophagocytosis and erythrocyte lysis, was assessed using antibiotic cocktail (ABX) gavage administered prior to ICH induction in mice. Flow cytometry analysis and targeted cell depletion techniques were employed to identify peripheral immune cell populations mediating the beneficial effects of gut microbiota depletion on neurological recovery and hematoma resolution. The functional roles of Tregs in erythrophagocytosis, erythrocyte lysis, and associated downstream molecular signaling pathways were investigated through adoptive Treg transfer experiments. The mechanisms underlying Treg population expansion post-microbiota depletion in ICH mice were explored using multi-omics analysis of serum and fecal metabolites via mass spectrometry and fecal microbial composition using 16S rRNA sequencing. Additionally, the effects of p-coumaric acid (PCA) gavage and clindamycin-mediated depletion of PCA-metabolizing gut microbiota on Treg abundance, hematoma resolution, and neurological recovery post-ICH were assessed. <b>Results:</b> Gut microbiota depletion by ABX gavage increased brain Treg populations, thereby enhancing erythrophagocytosis, suppressing erythrocyte lysis, and ultimately promoting hematoma resolution and neurological recovery. Adoptive Treg transfer experiments further established that Tregs facilitate scavenger pathway-mediated erythrophagocytosis and suppress complement-mediated erythrocyte lysis. These effects occurred via upregulation of efferocytosis receptors (MERTK and AXL), ligands (Gas6 and C1q), and the hemoglobin scavenger receptor CD163, alongside downregulation of complement C3 expression and reduced formation of membrane attack complexes (MACs). Multi-omics analysis demonstrated that ABX gavage eliminated PCA-metabolizing microbiota, thereby increasing PCA concentrations in serum and feces. Elevated PCA levels promoted peripheral Treg differentiation by inhibiting the PKCθ-AKT-FoxO1/3a signaling pathway, leading to higher brain Treg numbers. PCA gavage and clindamycin treatment similarly enhanced brain Treg populations, accelerat","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6628-6650"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529600","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":"NGR-modified nanovesicles target ALKBH5 to inhibit ovarian cancer growth and metastasis.","authors":"Cheng Du, DaLu Wang, Boquan Zhang, Yasong Zhao, Zheng He","doi":"10.7150/thno.107766","DOIUrl":"10.7150/thno.107766","url":null,"abstract":"<p><p><b>Background:</b> Immunotherapy resistance in ovarian cancer (OC) poses a significant clinical hurdle. This study aims to investigate the potential of NGR-modified biomimetic nanovesicles (NGR-BNVs) for delivering ALKBH5 siRNA to reverse this resistance. <b>Methods:</b> <i>In vitro</i> and <i>in vivo</i> experiments were conducted to assess the efficiency of NGR-modified nanovesicles in delivering ALKBH5 siRNA. OC cell proliferation was evaluated, and apoptosis induction was measured. A mouse xenograft model was utilized to examine the effects on tumor volume and metastasis. Tumor immune microenvironment (TIME) analysis was performed to determine changes in immune cell proportions and immunomodulatory factors. <b>Results:</b> NGR-modified nanovesicles effectively delivered ALKBH5 siRNA, leading to a significant inhibition of OC cell proliferation and apoptosis induction. Treated groups in the mouse xenograft model exhibited reduced tumor volume and decreased metastatic signals. Analysis of the immune microenvironment revealed an increased proportion of CD8⁺ T cells, reduced Tregs and MDSCs, and notable changes in key immunomodulatory factors. <b>Conclusion:</b> This study highlights the potential of NGR-modified BNVs for overcoming immunotherapy resistance in OC by delivering ALKBH5 siRNA, resulting in modulation of the immune microenvironment and promising therapeutic outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6702-6718"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529624","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 FRET-based off-on AIE nanoprobe enables instant and stain-free detection of hypoxic niches in tumor sections.","authors":"Chen Wang, Jun Shen, Muredili Muhetaer, Shenwu Zhang, Jin Sun, Zhonggui He, Yuequan Wang, Cong Luo","doi":"10.7150/thno.113038","DOIUrl":"10.7150/thno.113038","url":null,"abstract":"<p><p><b>Rationale:</b> Hypoxia is a critical hallmark of solid tumors, significantly influencing their diagnosis, treatment, and prognosis. Currently, instant and accurate detection of hypoxic niches in tumor sectioning remains a major challenge. Conventional tumor section staining methods lack reliability due to dynamic changes in hypoxic conditions during time-consuming sample processing. <b>Methods:</b> Herein, we develop a FRET-based off-on AIE nanoprobe for instant and stain-free detection of tumor hypoxic niches following intravenous administration. A dimeric AIEgen (TNNT) is synthesized by conjugating two tetraphenylethene (TPE) molecules via azobenzene (Azo). TNNT self-assembles into stable nanoassemblies (NAs) with favorable drug delivery and tumor accumulation. <b>Results:</b> Under normoxic conditions, fluorescence is quenched due to FRET between TPE and Azo, effectively \"turning off\" the AIE signal. Notably, the fluorescence recovers quickly following Azo cleavage under hypoxia <i>in vitro</i> and <i>in vivo</i>. Moreover, the AIE nanoprobe demonstrates an advantage over pimonidazole hydrochloride (HP3, a widely used hypoxia probe) in terms of <i>ex-vivo</i> hypoxia detection. Furthermore, it can also report the varying degrees of hypoxia in tumors of different sizes. <b>Conclusions:</b> This study offers a practical tool for point-of-care tumor hypoxia detection and relevant pathological analysis.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6651-6664"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529550","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":"X-ray stimulates NQO1-dependent cascade reactions to induce strong immunogenicity for MRI-guided cancer radio-chemodynamic-immunotherapy.","authors":"Li He, Jiao-Jiao Ma, Yi-Qun Wu, Chen-Guang Wang, Tong Lan, Lu Su, Lin Zhu, Shi-Wen Huang, Kai Deng, Yong-Chang Wei","doi":"10.7150/thno.110573","DOIUrl":"10.7150/thno.110573","url":null,"abstract":"<p><p><b>Background:</b> Immunogenicity activation is vital for radioimmunotherapy, but the short-term oxidative damage caused by precise radiation planning limits this effect. Chemodynamic therapy (CDT) with prolonged generation of hydroxyl radical (•OH) can initiate immunogenicity in combination with X-rays, however, its performance is constrained by tumor insufficient H2O2. <b>Methods:</b> Here, we propose to construct β-lapachone-based nanoparticles (β-Lap/Fe NPs) which initiate cascade reactions to generate high levels •OH for an extended period in tumor following X-ray irradiation. <b>Results:</b> β-Lap/Fe NPs, constructed by co-encapsulation of β-Lap and Fe3O4 nanoparticles in reactive oxygen species (ROS) responsive C16-S-mPEG2000 micelles, remain stable under normal conditions but rapid decompose and release β-Lap and Fe2+ when exposed to high level ROS. Upon X-ray irradiation, the upregulation of ROS and NAD (P) H: quinone oxidoreductase-1 (NQO1) in tumor cells accurately triggers β-Lap/Fe NPs to persistently generate high levels H2O2 and •OH for 12 hours, ultimately causing strong immunogenic cell death effects. Moreover, β-Lap/Fe NPs with excellent T2-weighted magnetic resonance imaging provide imaging reference for guiding precise X-ray radiation and predicting •OH generation. β-Lap/Fe NPs mediated radio-chemodynamic-immunotherapy remarkably against primary tumor growth, and further shows effective suppression on untreated distant tumors via the abscopal effect. <b>Conclusions:</b> In a word, this work proposed the simple but powerful strategy for cancer radio-chemodynamic-immunotherapy that combines X-ray and CDT to remote locally and visually actuated long-time production of H2O2 and subsequently persistent generation of •OH for initiating strong antitumor immune responses.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6768-6788"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529561","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":"Enhanced neoangiogenesis and balance of the immune response mediated by the Wilms' tumor suppressor WT1 favor repair after myocardial infarction.","authors":"Nicole Wagner, Ana Vukolic, Delphine Baudouy, Sophie Pagnotta, Jean-Francois Michiels, Kay-Dietrich Wagner","doi":"10.7150/thno.104329","DOIUrl":"10.7150/thno.104329","url":null,"abstract":"<p><p><b>Rationale:</b> Cardiac repair and regeneration are severely constrained in adult mammals. Several cell types have been identified as playing a role in cardiac repair. However, our understanding of the regulatory proteins common to these cell types and implicated in cardiac repair remains limited. <b>Methods:</b> Experimental myocardial infarctions (MI) were induced in mice by ligation of the left coronary artery. WT1 expression in different cell types was determined by immunofluorescent double-labelling. VE-cadherin-CreERT2 (VE-CreERT2) mice were crossed with Wt1^lox/lox animals to generate the VE-CreERT2;Wt1^lox/lox strain to knockout WT1 in endothelial cells. Wt1^lox/lox and Tie2-CreERT2 animals were crossed to generate Tie2-CreERT2;Wt1^lox/lox mice to delete WT1 in endothelial and myeloid-derived cells. <b>Results:</b> We show that the Wilms' tumor suppressor WT1 is expressed in progenitor cell populations, endothelial cells, and myeloid-derived suppressor cells (MDSCs) in mice following MI. Endothelial-specific knockout of WT1 results in reduced vascular density after MI but does not affect functional recovery. Conversely, combined knockout of WT1 in endothelial and myeloid-derived cells increases infarct size, cardiac hypertrophy, fibrosis, hypoxia, and lymphocyte infiltration. Notably, angiogenesis, infiltration of MDSCs, and cellular proliferation were diminished, and importantly, cardiac function was reduced. Mechanistically, in addition to the previously established role of WT1 in promoting the expression of angiogenic molecules, this transcription factor positively regulates the expression of Cd11b and Ly6G, which are crucial for MDSC invasion, migration and function thereby preventing overactivation of the immune response. <b>Conclusions:</b> Several molecules have been identified that are implicated in distinct aspects of cardiac repair following MI. The identification of WT1 as a transcription factor that is essential for repair mechanisms involving various cell types within the heart may potentially enable the future development of a coordinated repair process following myocardial infarction.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6593-6614"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529595","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":"Immuno-oncological interactions between meningeal lymphatics and glioblastoma: from mechanisms to therapies.","authors":"Nan Wen, Xiao Xiao, Huangjie Lu, Qingyuan Chen, Genghong He, Zhiyuan Qian, Jianfeng Zeng, Li Xiao","doi":"10.7150/thno.111972","DOIUrl":"10.7150/thno.111972","url":null,"abstract":"<p><p>The recent discovery of meningeal lymphatic vessels (MLVs) has revolutionized our understanding of immune regulation within the central nervous system (CNS), overturning the long-standing view of the brain as an immune-privileged organ. Glioblastoma (GBM), the most aggressive primary brain tumor, remains therapeutically intractable due to its highly immunosuppressive microenvironment and poor response to conventional and immune-based therapies. Emerging evidence suggests that MLVs play a crucial role in CNS immune surveillance, cerebrospinal fluid drainage, and solute clearance, all of which are directly linked to GBM pathophysiology. This review is motivated by the urgent need to explore novel therapeutic strategies that address GBM's immune escape and therapeutic resistance. We comprehensively analyze the bidirectional interactions between MLVs and GBM, including their role in antigen transport, T cell activation, and tumor dissemination. Furthermore, we evaluate the therapeutic potential of targeting MLVs through lymphangiogenic stimulation or as alternative routes for immune modulation and drug delivery. These approaches offer promising avenues to enhance anti-tumor immunity and may pave the way for next-generation treatment paradigms in GBM.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6983-7000"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529621","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":"Oxidative stress-mediated PANoptosis and ferroptosis: Exploration of multimodal cell death triggered by an AIE-active nano-photosensitizer via photodynamic therapy.","authors":"Yuqing Wang, Chuxing Chai, Wangxing Lin, Juanmei Cao, Zhuoxia Li, Yifan Jin, Yiting Xu, Jianyu Zhang, Yong Qu, Jinshan Zhan, Tianqi Zhao, Yufan Chen, Meng Gao, Changzheng Huang, Min Li","doi":"10.7150/thno.111635","DOIUrl":"10.7150/thno.111635","url":null,"abstract":"<p><p><b>Background:</b> Aggregation-induced emission (AIE)-based photodynamic therapy (PDT) represents a promising strategy for cancer treatment for its capacity to activate specific cell death pathways through pronounced oxidative stress. While the activation of specific death pathways has been correlated with PDT efficiency and overall effect, the systematic coordination of oxidative stress across different cell death modalities to amplify therapeutic effects remains unexplored. Current research lacks systematic investigation into how oxidative stress coordinates multiple cell death pathways to amplify therapeutic outcomes of PDT. <b>Methods:</b> We developed an AIE-based nano-photosensitizer (T-T NPs) to induce multimodal cell death through PDT. The system was characterized for mitochondrial targeting capability and reactive oxygen species (ROS) generation. Mechanistic analyses were conducted to evaluate programmed cell death pathways and ferroptosis induction in tumor. <b>Results:</b> T-T NPs exhibited superior mitochondrial targeting and highly efficient ROS generation. This dual effect successfully triggered PANoptosis and ferroptosis. The synergistic activation of these pathways significantly enhanced PDT-mediated antitumor efficacy. <b>Conclusion:</b> Our findings reveal that AIE-driven PDT can orchestrate multimodal cell death in tumor through oxidative stress modulation. By concurrently activating PANoptosis and ferroptosis, this approach establishes a novel paradigm for overcoming limitations of conventional single-pathway targeted PDT.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6665-6685"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529628","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":"Direct delivery of MRI contrast through skull vessel/marrow pathways into the brain guided by microCT.","authors":"Li Liu, Martin J MacKinnon, Tatjana Atanasijevic, Stephen Dodd, Nadia Bouraoud, Danielle Donahue, Harikrishna Rallapalli, Alan P Koretsky","doi":"10.7150/thno.117250","DOIUrl":"10.7150/thno.117250","url":null,"abstract":"<p><p><b>Rationale:</b> The brain remains a challenging organ for drug delivery. Earlier studies demonstrated that transcranial application of small molecular therapeutics and MRI contrast such as manganese ion (Mn²⁺) could serve as a new method for delivering molecules to the brain. In this earlier work using rats, manganese-enhanced MRI (MEMRI) demonstrated that Mn²⁺ passed most effectively through regions of the skull containing suture lines or dense vessel/marrow. In the present study, the delivery of Mn²⁺ to the brain using specific skull vessel/marrow pathways has been investigated. <b>Methods:</b> <i>In-vivo</i> microCT scans of rat skull was conducted to study the intricate geometry of vessel/marrow pathways connecting the outer skull surface and meninges. Specific vessel/marrow paths were identified. MnCl₂ (500 mM) solution was pipetted directly on the skull bone surface above the target path. After 2 hr, rats were subjected to MRI. <b>Results:</b> High-resolution microCT images reveal that (a) there are \"short paths\" through the skull which have vessels on the outer surface of the skull, which directly pass through the vessel/marrow and then reach the meninges on the other side of the skull; (b) the skull above the cerebellum (interparietal bone) exhibits a significantly higher density of vessel/marrow compared to the frontal and parietal bone enabling testing whether direct application to skull enables transcranial movement and (c) thinning the skull in specific regions can lead to exposing vessel pathways from mid-skull to the meninges. Guided by microCT imaging, Mn²⁺ delivery to the brain could be accomplished as assayed with MEMRI through these different specific pathways. Two hours post pipetting MnCl₂ solution onto the top of a short path through the intact skull, Mn²⁺ could be delivered readily to levels that produce detectable brain tissue enhancement by MEMRI. A T₁ enhanced volume of 2.27 ± 1.47 mm³ was measured through the short path. Two hours post applying a MnCl₂ solution to the intact skull above the cerebellum enabled MEMRI detection of a volume of enhanced brain tissue of 2.48 ± 2.66 mm³. Finally, in areas where surface short paths are absent but a path from mid skull to meninges is present, minimal thinning of the skull led to effective Mn²⁺ delivery, enabling MEMRI detection of volume of 4.68 ± 2.70 mm³. <b>Conclusions:</b> MicroCT-guided transcranial delivery via vessel/marrow pathways may offer a less invasive and more localized method for administering imaging probes and therapeutics to the brain.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6615-6627"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529592","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":"OTUD1 inhibits osteoclast differentiation and osteoclastic bone loss through deubiquitinating and stabilizing PRDX1.","authors":"Xiaoyu Sun, Tong Wu, Shuhong Chen, Zheyu Zhao, Ruiwei Jia, Jun Ma, Lei Yin, Xingbei Pan, Yifan Ping, Yixin Mao, Lulu Ma, Yilin Ma, Wu Luo, Shengbin Huang, Guang Liang","doi":"10.7150/thno.111360","DOIUrl":"10.7150/thno.111360","url":null,"abstract":"<p><p><b>Rationale:</b> Bone homeostasis relies on a delicate equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. Disruption of this balance leads to various disorders, most notably osteoporosis. Deubiquitinating enzymes (DUBs), which cleave ubiquitin moieties from substrate proteins, play critical regulatory roles in bone pathophysiology. In this study, we explored the function of a DUB, ovarian tumor deubiquitinase 1 (OTUD1), in bone remodeling. <b>Methods:</b> We examined the femur bone of <i>Otud1^+/+</i> and <i>Otud1^-/-</i> male mice using micro-CT analyses and histomorphometry. The potential functions and mechanisms of OTUD1 were explored in bone marrow-derived macrophages, RAW264.7 cells, and bone marrow stromal cells using RT-qPCR, western blotting and immunofluorescence. Additionally, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with co-immunoprecipitation (Co-IP) to identify OTUD1-interacting proteins and substrates. <b>Results:</b> Our results demonstrated a significant downregulation of both the gene and protein level of OTUD1 during osteoclastogenesis. Furthermore, both whole-body knockout and myeloid-specific deficiency of OTUD1 resulted in reduced bone mass in male mice, driven by enhanced osteoclast differentiation. Mechanistically, OTUD1 maintained the stability of peroxiredoxin 1 (PRDX1) by reversing K48-linked ubiquitination, thereby mitigating mitochondrial dysfunction and suppressing osteoclast differentiation. Consistent with these results, mitochondria-targeted ubiquinone (MitoQ), a mitochondria-targeted antioxidant, effectively suppressed bone mass loss in OTUD1-deficient male mice. <b>Conclusions:</b> Our findings provided the first evidence that OTUD1 suppressed osteoclastogenesis by deubiquitinating PRDX1 and maintaining its stability, thereby offering a promising therapeutic approach for osteoclast-dependent bone diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6719-6736"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529626","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":"Bioactive metal-protein matrix for promoting MRSA infection wound therapy through bioenergy-induced angiogenesis.","authors":"Sihua Li, Junping Ma, Liuyang Zhang, Xiaoyan Qu, Long Zhang, Qian Huang, Bo Lei","doi":"10.7150/thno.112678","DOIUrl":"10.7150/thno.112678","url":null,"abstract":"<p><p><b>Background:</b> Wound healing impaired by multidrug-resistant bacteria (MDRB) remains a significant clinical challenge, primarily due to persistent bacterial infection, excessive inflammation, overproduction of reactive oxygen species (ROS), and compromised vascularization. Importantly, the cellular metabolic state plays a vital role in regulating cellular behavior, and strategies aimed at enhancing cellular energy metabolism hold great promise for promoting tissue regeneration. <b>Methods:</b> Herein, we present a multifunctional and bioactive silk fibroin-poly(citrate-curcumin)-metal-based biomimetic matrix (SFPC) designed to treat methicillin-resistant staphylococcus aureus (MRSA)-infected wounds by promoting bioenergy-induced angiogenesis. <b>Results:</b> SFPC exhibited robust broad-spectrum antimicrobial, anti-inflammatory, intracellular ROS-scavenging, and pro-angiogenic properties. Notably, SFPC effectively enhanced mitochondrial membrane potential and promoted adenosine triphosphate (ATP) production in HUVECs, thereby accelerating angiogenesis through the controlled release of citrate. <b>Conclusions:</b> This study suggests that SFPC is a promising alternative for the treatment of MRSA infected wounds and provides a facile approach for the development of a multifunctional hydrogel that promotes the healing of MRSA infected wounds at the level of cellular energy biology.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6882-6900"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529554","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}