Theranostics最新文献

{"title":"Epigenetic and O-glycosylation regulation of p66Shc mitigates mitochondrial oxidative stress in aortic dissection.","authors":"Wenjun Zhang, Wanjun Liu, Xiaodan Zhong, Lei Dai, Xiaolei Liu, Shiliang Li, Hongcheng Jiang, Xingwei He, Wei Dong, Lijuan Lu, Li Zhu, Thati Madhusudhan, Hongjie Wang, Hesong Zeng","doi":"10.7150/thno.124508","DOIUrl":"10.7150/thno.124508","url":null,"abstract":"<p><p><b>Background:</b> Aortic dissection (AD) is a life-threatening vascular emergency with limited effective pharmacological treatments. Recent studies have identified Src homology 2 domain-containing transforming protein C1 (p66Shc) as a crucial mediator of oxidative stress, apoptosis, and inflammation in aortic cells, thereby contributing to cellular dysfunction and vascular remodeling implicated in AD development and progression. Despite its established role in promoting vascular dysfunction and remodeling, the protective potential of targeting p66Shc in AD remains unclear. <b>Methods:</b> We quantified activated protein C (aPC) levels in clinical plasma samples from control subjects and AD patients using enzyme-linked immunosorbent assay (ELISA). To evaluate changes in p66Shc expression, we analyzed aortic tissues by Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) staining. An <i>in vivo</i> AD model was established in thrombomodulin (TM)-mutant ApoE^-/- mice, which display impaired TM-dependent PC activation, and exogenous PC was administered to evaluate its therapeutic effect. In parallel, mechanistic studies were performed in human endothelial cells using WB, co-immunoprecipitation (Co-IP), dual-label IF staining, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and mitochondrial functional analyses. <b>Results:</b> In this study, we demonstrate that aPC, a coagulation protease with known cytoprotective properties, downregulates <i>p66Shc</i> expression through epigenetic modifications. Additionally, aPC can modulate the expression of a cold shock protein Y-box-binding protein 1 (YB1), which acts as a transcription factor, leading to elevated O-linked N-acetylglucosamine transferase (OGT) levels. This upregulation enhances the O-glycosylation of p66Shc on its 29th tyrosine residue, preventing its mitochondrial translocation, preserving mitochondrial membrane potential, and reducing reactive oxygen species (ROS) production. Consequently, these molecular mechanisms inhibit the onset and progression of AD. <b>Conclusions:</b> aPC epigenetically represses p66Shc transcription and promotes its O-glycosylation at Thr29 <i>via</i> the YB-1/OGT axis, thereby inhibiting mitochondrial ROS production and preventing vascular injury.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4394-4410"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202534","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":"Harnessing nucleotide metabolism to control glycosylase base editing outcomes.","authors":"Rui Tao, Min Li, Junyi Fei, Minhai Tang, Zhi Yang, Yun Hu, Yaoge Jiao, Zhangxue Hu, Shaohua Yao","doi":"10.7150/thno.125705","DOIUrl":"10.7150/thno.125705","url":null,"abstract":"<p><strong>Rationale: </strong>Glycosylase-derived base editors enable transversion base substitutions, expanding the scope of genome engineering for both basic research and clinical applications. However, the variable outcomes and low efficiency of B (C/G/T)-to-A editing in mammalian cells hinder their broader utility, likely due to inefficient thymine translesion synthesis (TLS) across apurinic/apyrimidinic (AP) sites.</p><p><strong>Methods and results: </strong>We developed a nucleotide metabolism-based strategy to enhance B-to-A editing by leveraging endogenous nucleotide metabolism. We showed that elevating intracellular deoxythymidine triphosphate (dTTP) levels via exogenous thymidine (dT) supplementation, which activates the thymidine kinase 1 (TK1)-dependent salvage pathway for the production of dTTP, increased C-to-A, G-to-A, and T-to-A editing efficiencies by up to 4-fold, 1.8-fold, and 1.8-fold, respectively, and improved A-product purity by up to 2.7-fold. Moreover, supplementation with dA increased T outcomes, albeit at a relatively modest level. In a disease-relevant single nucleotide variation (SNV) model, dT treatment enabled efficient generation of pathogenic mutations otherwise inaccessible to base editing.</p><p><strong>Conclusion: </strong>Our findings establish metabolic modulation as a powerful means to control base editing outcomes and expand the functional capabilities of glycosylase-derived editors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4411-4426"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202652","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":"Histone H4K8 lactylation promotes glioblastoma progression by inducing NUPR1-mediated autophagosome‒lysosome fusion.","authors":"Jiangli Zhao, Xuchen Liu, Yanya He, Qingyuan Sun, Zhiwei Xue, Ziyi Tang, Junzhi Liu, Jiwei Wang, Chao Li, Xinyu Wang, Ning Yang, Chen Qiu","doi":"10.7150/thno.126579","DOIUrl":"10.7150/thno.126579","url":null,"abstract":"<p><p><b>Rationale:</b> Glioblastoma (GBM), an aggressive malignant brain tumour associated with a dismal prognosis, is characterized by metabolic reprogramming that drives tumour progression, with the Warburg effect being a central contributor. This effect not only causes significant lactate buildup but also fuels lactylation, a novel post-translational modification implicated in the development of gliomas and various other cancers. Nevertheless, the exact molecular mechanisms by which lactylation promotes GBM progression remain largely elusive. <b>Methods:</b> Lactylation levels in normal brain and GBM tissues were analysed using immunohistochemistry, immunofluorescence, and Western blotting. Glycolysis inhibitors and LDHA/LDHB knockdown were used to modulate histone lactylation in subsequent <i>in vitro</i> and <i>in vivo</i> experiments assessing GBM cell proliferation, invasion, and migration. CUT&Tag and RNA sequencing were used to identify H4K8la target genes, and NUPR1 expression was validated via ChIP‒qPCR and Western blotting. Autophagic flux was examined using transmission electron microscopy, EGFP-mCherry-LC3B probes, and LysoTracker staining. The therapeutic effects of NUPR1 inhibitor ZZW-115 were evaluated in both cellular and animal models. <b>Results:</b> Histone lactylation, notably that of H4K8la, was markedly increased in GBM cells. Targeting lactate metabolism and lactylation levels attenuated GBM malignancy <i>in vitro</i> and <i>in vivo</i>. Genome-wide analysis revealed H4K8la enrichment at promoter regions, where it transcriptionally activated the autophagy regulator NUPR1. Functionally, NUPR1 enhanced protective autophagy via autophagosome‒lysosome fusion. Pharmacological inhibition of NUPR1 with ZZW-115 suppressed GBM growth by impairing autophagic flux, demonstrating therapeutic potential. <b>Conclusion:</b> In summary, this study defines the functional and prognostic significance of histone lactylation in the progression of GBM. We identified the H4K8la-NUPR1 axis as a key regulatory pathway that mediates protective autophagy and developed targeted therapeutic strategies to disrupt this pathway. These findings provide novel insights into epigenetic regulation and targeted therapy for GBM.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4427-4451"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202642","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":"Cardiomyocyte-derived OTUD7B promotes cardiac hypertrophy by deubiquitinating SERCA2a.","authors":"Zhuqi Huang, Xue Han, Yuxing Hou, Xingchen Wang, Fuyu Qiu, Yingchao Gong, Nipon Chattipakorn, Guosheng Fu, Guang Liang, Dongwu Lai","doi":"10.7150/thno.129105","DOIUrl":"10.7150/thno.129105","url":null,"abstract":"<p><p><b>Rationale:</b> Pathological cardiac hypertrophy, triggered by persistent neurohumoral or hemodynamic stress, is a key precursor of ventricular dysfunction and heart failure. Deubiquitinating enzymes (DUBs) have emerged as critical regulators of cardiovascular biology. This study examined the function of a DUB, ovarian tumor domain-containing 7B (OTUD7B), in cardiac hypertrophy. <b>Methods:</b> Cardiomyocyte-specific OTUD7B knockout and overexpression mouse models were generated to evaluate myocardial hypertrophy and cardiac dysfunction in response to angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Quantitative ubiquitinome analysis, site-directed mutagenesis, and co-immunoprecipitation assays were performed to explore the substrate and mechanism of OTUD7B. <b>Results:</b> Transcriptomic and experimental validation demonstrated that cardiomyocyte OTUD7B was increased in hypertrophic hearts of both humans and mice. Cardiomyocyte-specific deletion of OTUD7B significantly mitigated angiotensin II (Ang II)- and transverse aortic constriction (TAC)-induced cardiac hypertrophy and dysfunction in mice. Mechanistically, quantitative ubiquitinome analysis identified sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a) as a direct substrate of OTUD7B. OTUD7B bound to SERCA2a and removed K63-linked ubiquitin at K628 through its catalytic site C194. This deubiquitination promoted SERCA2a-phospholamban (PLN) interaction, thereby restricting SERCA2a activity in Ca²⁺ handling and driving hypertrophic response in cardiomyocytes. Moreover, cardiomyocyte-specific OTUD7B overexpression exacerbated TAC-induced cardiac hypertrophy and dysfunction by deubiquitinating SERCA2a at K628. <b>Conclusions:</b> This study defines a novel OTUD7B-SERCA2a regulatory axis and identifies OTUD7B as a promising therapeutic target for cardiac hypertrophy and dysfunction.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4452-4470"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202175","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":"MUC20 alleviates kidney fibrosis by modulating pyroptosis through the MET/RAS/STING axis.","authors":"Jiaxin Huang, Zhoutong Chen, Fengbo Zhong, Rui Zheng, Dexin Zhang, Jingyi Su, Yi Zhong, Xiaoliang Fang, Dali Li, Yuting Guan, Hongquan Geng","doi":"10.7150/thno.123986","DOIUrl":"10.7150/thno.123986","url":null,"abstract":"<p><p><b>Rationale:</b> Mucins are epithelial transmembrane glycoproteins involved in inflammation and kidney dysfunction, yet the role of the transmembrane mucin MUC20 in renal injury and fibrosis remains unclear. This study aimed to define the functional significance and underlying mechanisms of MUC20 in kidney fibrosis. <b>Methods:</b> <i>Muc20</i>-deficient mice and tubular epithelial cell models were used to evaluate renal fibrosis and pyroptosis in induced kidney injury. Molecular and biochemical approaches were applied to assess protein interactions, RAS activation, 2'3'-cGAMP production, cGAS-STING signaling, lysosomal integrity, potassium efflux, and NLRP3 inflammasome activation. <b>Results:</b> Loss of MUC20 significantly exacerbated renal fibrosis and increased pyroptosis in tubular epithelial cells. Mechanistically, MUC20 interacted with MET to promote RAS activation. MUC20 deficiency decreased GTP-bound RAS levels, leading to increased 2'3'-cGAMP production and activation of the cGAS-STING pathway. STING activation induced lysosomal membrane permeabilization, potassium efflux, and subsequent NLRP3 inflammasome-mediated pyroptosis. <b>Conclusions:</b> MUC20 acts as a key protective regulator in kidney by restraining RAS-cGAS-STING-NLRP3-driven pyroptosis and fibrotic progression. Targeting MUC20-related signaling pathways may offer therapeutic potential for kidney fibrosis and chronic kidney disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4374-4393"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202610","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":"Specific <i>in vivo</i> detection of V2R-positive metastatic ccRCC using a toxin-based PET radioligand.","authors":"Goran Stanajic Petrovic, Khawla Chmeis, Alix Gonand, Ingrid Leguerney, Alexandre Ingels, Dimitri Kereselidze, Benoit Jego, Caroline Denis, Apolline Urman, Marion Chaigneau, Romain Baudat, Antoine Guyot, Pascal Kessler, Mathilde Keck, Denis Servent, Mylène Richard, Nicolas Gilles, Charles Truillet","doi":"10.7150/thno.126311","DOIUrl":"10.7150/thno.126311","url":null,"abstract":"<p><strong>Background: </strong>The diagnosis of metastatic clear cell renal cell carcinoma (mccRCC) remains challenging due to the tumor's molecular heterogeneity, often resulting in low sensitivity and a high false-positive rate. In this study, we introduce and validate a new imaging modality for mccRCC based on the first radioligand targeting the type 2 vasopressin receptor (V2R) suitable for positron emission tomography (PET). V2R is ectopically expressed in mccRCC. This imaging approach utilizes [¹⁸F]F-MQ232, a radiolabeled peptide derived from snake venom which exhibits high <i>in vivo</i> selectivity for V2R.</p><p><strong>Methods: </strong>The V2R-selective peptide MQ232 conjugated with either a cyanine 5 (Cy5) or a fluorine 18 (¹⁸F) group were chemically synthetized. V2R mRNA was quantified and protein expression assessed by flow cytometry using Cy5-MQ232. The selectivity and tumor targeting ability of the modified MQ232 peptides were assessed using <i>in vivo</i> fluorescence imagery in tumor-bearing mice using CHO-V2R tumors with graded expression. Metabolic stability and PET pharmacokinetics of [¹⁸F]F-MQ232 were assessed in rodents. Specific tumor targeting and imaging contrast were validated <i>in vivo</i> using V2R-expressing tumors.</p><p><strong>Results: </strong>[¹⁸F]F-MQ232 is a highly relevant radioligand whose tumor uptake directly correlates with V2R expression levels in tissues, demonstrating its specificity to V2R-expressing tumors. Replacing the peptide moiety by an isoform unable to interact with V2R leads to a drastic decrease in the radioligand's tumor uptake, highlighting its origin in a specific, ligand/receptor type interaction between the MQ232 moiety and V2R. PET/CT imaging of Caki-1 xenografted mice demonstrated the ability of [¹⁸F]F-MQ232 to allow specific detection of the tumor compartment associated with high tumor-to-background contrast. RT-qPCR screening of metastatic and non-metastatic ccRCC biopsies from patients confirms V2R expression.</p><p><strong>Conclusions: </strong>This work validates the V2R-targeting strategy in mccRCC using [¹⁸F]F-MQ232 and demonstrates that human mccRCC tissues express V2R, confirming the suitability of this specific imaging technique for metastasis extension assessment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 9","pages":"4471-4488"},"PeriodicalIF":13.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12964010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378661","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":"Erratum: Improved Tumor Targeting and Longer Retention Time of NIR Fluorescent Probes Using Bioorthogonal Chemistry: Erratum.","authors":"Xianghan Zhang, Bo Wang, Na Zhao, Zuhong Tian, Yunpeng Dai, Yongzhan Nie, Jie Tian, Zhongliang Wang, Xiaoyuan Chen","doi":"10.7150/thno.128809","DOIUrl":"https://doi.org/10.7150/thno.128809","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/thno.20912.].</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4306-4307"},"PeriodicalIF":13.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202560","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":"Sono-piezoelectric cues regulate neuroinflammatory reflex-arc-mediated α7nAChR-P2RX7 axis to dampen osteoarthritis-correlated pain with osteoarthritis attenuation.","authors":"Qiuling Zhong, Junqi Xie, Maocheng Zuo, Chuanan Liao, Qiuxia Peng, Simeng Yu, Pan Hu, Yuanyuan Liu, Li Zheng, Kun Zhang, Zhenhui Lu, Jinmin Zhao","doi":"10.7150/thno.125686","DOIUrl":"10.7150/thno.125686","url":null,"abstract":"<p><p><b>Background:</b> Osteoarthritis (OA) characterized by progressive cartilage degeneration and chronic pain is hindered by the vicious inflammation-pain cycle. Nonsteroidal anti-inflammatory drugs (NSAIDs) can only alleviate clinical symptoms. Although electrical stimulation of the vagus nerve has achieved some results, the toxicity of the electrodes and the secondary damage caused by dismantling limited its clinical application. <b>Methods:</b> A \"sono-piezoelectric-bioelectricity-neuroimmune\" cascade modulation strategy based on ultrasound-driven piezoelectric ZnO nanoparticles was established to attenuate osteoarthritic neurogenic inflammation and pain with inhibited cartilage degradation. <b>Results:</b> The \"sensory neuron-cholinergic anti-inflammatory pathway\" reflex arc was activated by the dynamically and spatially-temporally programmed sono-piezoelectric field (0.7 V/36 μA peak) within deep joint tissues by targeting α7nAChR-P2RX7 neuroimmune axis. Consequently, our sono-piezoelectric neuroimmune modulation strategy significantly up-regulated α7nAChR expression, and synchronously inhibited pain mediator CX3CL1, opposed macrophage infiltration, inhibited P2RX7-mediated IL-1β/IL-6 inflammatory storm, restored IL-1β-injured chondrocyte activity and migration capacity, activated stromal genes (Col2a1) for matrix synthesis, and inhibited cartilage degradation-related MMP13 expression. All these actions re-established the balance of glycosaminoglycan (GAG)/deoxyribonucleic acid (DNA) metabolism to remodel joint immune homeostasis, and activated the cholinergic pathway to break the vicious cycle of \"inflammation-pain\", which restored mechanical pain threshold (Von Frey) and weight-bearing capacity to near-normal levels and reconstructed tidal structures in a rat OA model. <b>Conclusions:</b> Our pioneering \"sono-piezoelectrical signal-neural reflex-immunomodulation\" cascade strategy for regulating neuroinflammatory reflex-arc-mediated α7nAChR-P2RX7 axis provide deep insights into OA-represented neuroinflammatory diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4358-4373"},"PeriodicalIF":13.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202658","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":"Systemic CSF1R Targeting Depletes Pathogenic MPS Bubs and Ameliorates Psoriasis via PPARα-mediated Resolution.","authors":"Zhen-Jia Lin, Ying Li, Yangyinhui Yu, Mei-Jia Fang, Ying Xiong, Rui Xu, Zhuo Wang, Jun Zhang, Ya-Nan Xu, Jun-Ya Wan, Xiang Ji, Yu-Fan Zheng, Kai-Lang Zhang, Ming Wei, Jun-Tao Zou, Li-Xuan Jia, Hui Zhang, Chang-Lin Li, Li-Jun Zhou, Zhi Tan","doi":"10.7150/thno.128248","DOIUrl":"10.7150/thno.128248","url":null,"abstract":"<p><p><b>Rationale:</b> Psoriasis features persistent activation of the mononuclear phagocyte system (MPS), yet the subset-specific pathogenic roles of colony-stimulating factor 1 receptor (CSF1R) remain undefined. We aimed to identify pathogenic CSF1R^high MPS subsets, characterize their ligand-receptor circuits, and define the CSF1R-PPARα axis in disease pathogenesis. <b>Methods:</b> By integrating human single-cell and spatial transcriptomics with murine imiquimod (IMQ)-induced psoriasis models, we employed genetic and pharmacologic interventions to achieve our aims. <b>Results:</b> We found a pathologic CSF1R^high MPS population was selectively expanded, forming localized cytokine hubs enriched for TNF-α, IL-1β, and IL-23. Ligand mapping showed CSF1 upregulation amplified MPS activation via autocrine loops. Systemic CSF1R targeting dismantled skin-blood MPS circuits and depleted pathogenic hubs, suppressing pro-inflammatory cytokines more effectively than local blockade. Mechanistically, CSF1R activation directly suppressed PPARα. Critically, the anti-inflammatory effect of CSF1R inhibition was abrogated by PPARα antagonism, demonstrating a non-redundant, downstream role for PPARα. Consequently, CSF1R suppression releases PPARα-mediated resolution programs. Pathogenic CSF1R^high MPS hubs sustain inflammation through ligand-driven expansion and PPARα suppression. <b>Conclusions:</b> Our work delineates a unidirectional CSF1R-PPARα pathogenic axis and demonstrates that systemic CSF1R targeting is required to disrupt this circuit, providing a mechanistic foundation for a novel treatment strategy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4336-4357"},"PeriodicalIF":13.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202700","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":"Therapeutic Promise of Mitophagy in Cancer: Advancing from Small-Molecule Regulation to Nanotechnology-Enhanced Targeting Therapy.","authors":"Ping Chen, Guohao Liu, Jiani Yin, Ling Sun, Xiaoming Wang, Bing Wang, Qiyong Gong, Kui Luo","doi":"10.7150/thno.129867","DOIUrl":"10.7150/thno.129867","url":null,"abstract":"<p><p>Mitophagy, a selective autophagic pathway that clears damaged or dysfunctional mitochondria, has emerged as a promising therapeutic approach. Mitophagy maintains a delicate balance between cell survival and death, while mounting evidence suggests that it predominantly promotes tumor cell survival under stress, particularly in responses to cancer therapy. Moreover, aberrant regulation of mitophagy results in cancer pathology with characteristic hallmarks, including remodeling of metabolic plasticity, maintenance of cancer stem cell characteristics, and immune regulation of the tumor microenvironment. This review synthesizes multifaceted roles of mitophagy in cancer biology, from tumor initiation and progression to therapy responses. It also summarizes molecular mechanisms underlying mitophagy. How cancer cells exploit mitophagy to survive therapy has been harnessed to develop therapeutic strategies. We elaborate the evolution of mitophagic therapy from small-molecule modulators to nanotechnology-based targeted delivery systems. Finally, we highlight the promise of targeting mitophagy in overcoming treatment resistance and improving clinical outcomes for patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"16 8","pages":"4308-4335"},"PeriodicalIF":13.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202780","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}