tbuckley/cabot-search huggingface dataset:
Colorectal cancer stem cells develop NK cell resistance via homotypic cell-in-cell structures suppressed by Stathmin1
Authors: Yen-Yu Lin, Hsin-Yi Lan, Hao-Wei Teng, Ya-Pei Wang, Wen-Chun Lin, Wei-Lun Hwang
Journal: Theranostics (2025)

Rationale: Advances in cancer therapies have significantly improved patient survival; however, tumors enriched in cancer stem cells (CSCs) have poor treatment responses. CSCs are a key source of tumor heterogeneity, contributing to therapeutic resistance and unfavorable patient outcomes. In the tumor microenvironment (TME), cell-in-cell (CIC) structures, where one cell engulfs another, have been identified as markers of poor prognosis. Despite their clinical relevance, the mechanisms underlying CIC formation across different tumor cell subpopulations remain largely unknown. Elucidating these processes could provide novel insights and therapeutic opportunities to address aggressive, treatment-resistant cancers. Method: Fluorescent mCherry-carrying colorectal cancer stem cells (CRCSCs) were expanded as spheroids in serum-free media and cocultured with either parental cancer cell-expressing Venus fluorescent protein or CFSE dye-stained immune cells (T cells, M1/M2 macrophages, neutrophils, and NK cells) or treated with EGFR- or PD-L1-targeting antibodies to assess the formation of CIC structures. Genes potentially crucial for the formation of CIC structures were knocked down or overexpressed, and their effects on CIC formation were evaluated. The clinical relevance of the in vitro findings was confirmed through analysis of formalin-fixed, paraffin-embedded (FFPE) human colorectal cancer (CRC) specimens. Results: CRCSCs have a strong predilection for serving as the outer cell in a CIC structure and forming homotypic CIC structures predominantly with parental CRC cells. The frequency of CIC structure formation increased when the cells were exposed to anti-PD-L1 antibody treatment. Both the outer CRCSC in a CIC structure and CRCSCs released from a homotypic CIC structure showed enhanced resistance to the cytotoxicity of NK-92MI cells. Restoration of Stathmin1 (STMN1) expression but not RAC1 knockdown in CRCSCs reduced the homotypic CIC frequency, disrupted the outer cell fate in CIC structures, and increased cell susceptibility to NK-92MI cytotoxicity. In CRC patients, CIC structures are associated with poor tumor differentiation, negative STMN1 expression, and poor prognosis. Conclusion: CSCs play a crucial role in informing CIC structures in CRC. CIC structure formation partially depends on low STMN1 expression and confers a survival advantage under NK cytotoxicity. Targeting this pathway may significantly improve immunotherapy's efficacy for CRC patients.
Modulation of brain immune microenvironment and cellular dynamics in systemic inflammation
Authors: Junhao Wang, Zhaoqian Zhong, Haihua Luo, Qizheng Han, Kan Wu, Aolin Jiang, Li Chen, Yanxia Gao, Yong Jiang
Journal: Theranostics (2025)

Background: Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, affecting approximately 70% of patients, leading to increased mortality and long-term cognitive impairments among survivors. However, there is a lack of comprehensive studies on the development of SAE, especially related to the cellular communication networks in the brain microenvironment. Methods: We evaluated the impact of myeloid cells on the brain's immune microenvironment through glial cell alterations using bulk and single-cell transcriptomics data from human and mouse models and validated this with correlative experiments. We also developed the DeconvCellLink R package to study neuroinflammation-associated cellular interaction networks. A dynamic brain immune microenvironment map showing temporal alterations in brain cellular network during systemic inflammatory reactions was constructed using time-series data. Results: While brain cellular alterations differed between human and animal models, a highly conserved set of sepsis-associated genes regulating immune microenvironment signalling was identified. The dynamic alterations in cellular interaction networks and cytokines revealed brain immune cells' temporal response to systemic inflammation. We also found that valproic acid could mitigate sepsis-induced neuroinflammation by regulating glial cell balance and modulating the neuroimmune microenvironment. Conclusion: Through dynamic cellular communication networks, the study revealed that, immune dysregulation in the inflamed brain in SAE involves overactivation of innate immunity, with neutrophils playing a crucial role, providing a scientific framework for developing novel therapeutic strategies and offering new insights into the mechanisms underlying sepsis-induced brain dysfunction.
The basolateral amygdala-anterior cingulate cortex circuit contributes to postherpetic neuralgia-anxiety comorbidity
Authors: Xiaofeng Jiang, Yi Yan, Ziming Chen, Jiaxin Xiong, Xuexue Zhang, Lili Gu, Yong Zhang, Mengye Zhu, Daying Zhang, Jian Jiang
Journal: Theranostics (2025)

Background: Postherpetic neuralgia (PHN) causes chronic pain and emotional dysfunction, but its underlying mechanisms are unknown. Methods: We first compared the structural and functional magnetic resonance imaging (MRI) of PHN-anxiety patients with healthy controls (HCs). Then, we created a PHN comorbid anxiety-like model by injecting resiniferatoxin (RTX) intraperitoneally and used Fos-CreER::Ai9 mice to validate brain regions with volume differences in MRI. Furthermore, we combined behavioral experiments with electrophysiology, viral tracing, in vivo fiber-photometry, optogenetics, and chemogenetics, to analyze the role of the basolateral amygdala (BLA)-anterior cingulate cortex (ACC) circuit in PHN comorbid anxiety-like mice multi-dimensionally. Results: According to neuroimages, patients with PHN-anxiety comorbidity have decreased amygdala volume and decreased functional connection (FC) of the BLA and ACC. Furthermore, we created a PHN comorbid anxiety-like model by injection of RTX intraperitoneally, and these mice showed dysesthesia and anxiety-like behaviors 3 weeks after RTX injection. Then, we discovered that BLA and ACC were related to PHN comorbid anxiety-like behaviors using Fos-CreER::Ai9 mice. Immunohistochemistry and electrophysiology revealed enhanced activation of BLA glutamatergic (BLAGlu) neurons in PHN comorbid anxiety-like mice. Opto/chemogenetic activating BLAGlu neurons aggravated pain threshold in PHN comorbid anxiety-like mice. Inhibiting BLAGlu alleviates mechanical nociception, thermal hyperalgesia, and anxiety-like behavior. Moreover, the elevated excitability of BLAGlu neurons resulted in increased excitatory inputs to the ACC. Selective activation or inhibition of the BLAGlu-ACC pathway exacerbated or alleviated the pain and anxiety behavior, respectively. Conclusion: Findings in this study will provide new insight for understanding the central pathomechanism underlying PHN-anxiety comorbidity, as well as serve as solid theoretical underpinnings for the management of PHN.
Leveraging adenosine triphosphate for cancer theranostics
Authors: Yuhan Li, Xinyu Zhang, Jianhua Wang, Kexin Wang, Boya Li, Xianghe Qiao, Wei He, Jinghua Cai, Danfeng Liu, Lei-Lei Yang
Journal: Theranostics (2025)

Manipulation of the biochemical composition of the tumor microenvironment (TME) is a thriving research area in cancer treatment. Adenosine triphosphate (ATP), a key biochemical component, serves as an energy source for cancer cell proliferation. Notably, ATP can also act as a potent signal transducer to prime anti-tumor immune responses. There is increasing attention given to both the tumor-promoting and tumor-inhibiting roles of ATP in the context of possible new treatments for cancer. ATP levels in the TME are known to be significantly greater than in non-tumor tissues. This disparity presents an opportunity to exploit the ATP response for the delivery of anti-tumor drugs and tumor diagnosis. In this article, we provide a comprehensive overview of the existing strategies and mechanisms for ATP-based therapy and cancer diagnosis. We also discuss the current challenges in the field and propose potential areas for future research, to provide researchers with insights to further investigate the potential of ATP in cancer theranostics.
Hyperglycemia-induced DNA damage response activates DNA-PK complex to promote endothelial ferroptosis in type 2 diabetic cardiomyopathy
Authors: Cheng Luo, Chen Fang, Rongjun Zou, Jingwei Jiang, Miao Zhang, Teng Ge, Hao Zhou, Xiaoping Fan, Baoshi Zheng, Zhiyu Zeng
Journal: Theranostics (2025)

Rationale: Hyperglycemia-induced endothelial dysfunction is a hallmark of diabetic cardiomyopathy, yet the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate how the DNA damage response (DDR) pathway regulates endothelial cell ferroptosis under hyperglycemic conditions, potentially revealing new therapeutic targets for mitigating cardiac damage in type 2 diabetes mellitus (T2DM). Methods: We performed an integrated analysis of publicly available RNA sequencing datasets (GSE280770, GSE89475, GSE161931, CRA007245) to evaluate the role of DDR in hyperglycemia-induced endothelial dysfunction in vitro and in vivo, including in a T2DM mouse model. Key DDR and ferroptosis markers were validated in cardiac microvascular endothelial cells (CMECs) isolated from mice with streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM, with and without treatment with the DNA-PK inhibitors NU7441 or M9831. Results: Hyperglycemia induced a robust DDR in endothelial cells, characterized by the upregulation of DNA-PK complex genes (PRKDC, XRCC5, XRCC6) and increased markers of DNA damage (γH2AX, 8-oxo-dG). This was accompanied by increased expression of pro-ferroptotic genes (Tfrc, Acsl4, Ptgs2), decreased expression of anti-ferroptotic genes (Gpx4, Slc7a11), and elevated lipid peroxidation (MDA, 4-HNE). Pharmacological inhibition of DNA-PK mitigated these effects, reducing oxidative stress, lipid peroxidation, and endothelial permeability, while improving cardiac contractile and relaxation parameters. Conclusions: Our findings implicate the DNA-PK complex as a key regulator of hyperglycemia-induced endothelial ferroptosis in T2DM cardiomyopathy. Targeting DNA-PK complex may represent a novel therapeutic strategy for mitigating microvascular dysfunction and cardiac decline in T2DM.
A brain-accessible peptide modulates stroke inflammatory response and neurotoxicity by targeting BDNF-receptor TrkB-T1 specific interactome
Authors: Lola Ugalde-Triviño, Gonzalo S Tejeda, Gema M Esteban-Ortega, Margarita Díaz-Guerra
Journal: Theranostics (2025)

Glia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Given the high incidence of these pathologies and the limited efficacy of current treatments, developing brain-protective therapies that target both neurons and glial cells is a priority. Truncated neurotrophin receptor TrkB-T1, a protein produced by these cell types, plays relevant roles in excitotoxicity and ischemia. We hypothesized that interactions mediated by isoform-specific TrkB-T1 sequences might contribute to neurotoxicity and/or reactive gliosis, thus representing potential therapeutic targets. Methods: We designed cell-penetrating peptides containing TrkB-T1 isoform-specific sequences to: 1) characterize peptide delivery into rat primary cortical cultures and mice brain cortex; 2) isolate and identify the isoform interactome in basal and in vitro excitotoxic conditions; 3) analyze peptide effects on neuroinflammation and neurotoxicity using primary cultures subjected to excitotoxicity or in vivo in a mouse model of ischemia. Results: We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can reduce reactive gliosis and decrease excitotoxicity-induced damage in cellular and animal models of stroke, where treatment reduces the infarct volume in male and female mice. Conclusions: The crucial role of TrkB-T1 in modulating microglia and astrocyte reactivity indicates that isoform-derived peptides hold promise for the development of therapies for human stroke and other excitotoxicity-associated pathologies.
Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection
Authors: Soo-Jin Oh, Young Yeon Kim, Ruiying Ma, Seok Tae Choi, Se Myeong Choi, Jong Hyun Cho, Ji-Yeun Hur, Yongjin Yoo, Kihoon Han, Hosun Park, Jeanho Yun, Ok Sarah Shin
Journal: Theranostics (2025)

Rationale: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of dysfunctional mitochondria. Herpes simplex virus type 1 (HSV1) may be a risk factor for the neuropathology linked to amyloid β (Aβ) accumulation. However, the mechanisms underlying HSV1-associated mitochondrial dysfunction in AD remain unclear. ALT001 is a novel drug that ameliorates AD-related cognitive impairment via ULK1/Rab9-mediated alternative mitophagy. In this study, we investigated the effects of ALT001 on the neurodegeneration-related microglial signatures associated with HSV1 infection. Methods: Molecular mechanisms and physiological functions of mitophagy was investigated in HSV1-infected microglia, including primary murine and human embryonic stem cell (ESC)-derived microglia (ES-MG), as well as in a microglia-neuron co-culture system. Microglial gene signatures following HSV1 infection in the presence or absence of ALT001 were analyzed using bulk RNA sequencing, and the effects of ALT001 on microglial phagocytosis and microglia-mediated immune responses were further evaluated by flow cytometry and cytokine profiles. Results: HSV1 infection inhibited PINK1/Parkin-mediated mitophagy via HSV1-encoded protein kinase US3, resulting in mitochondrial dysfunction in both human and mouse microglia. Furthermore, transcriptomic analysis of HSV1-infected microglia revealed an upregulation of distinct microglial genes associated with disease-associated microglia (DAM)-like phenotype and pro-inflammatory activity. Pharmacological targeting of mitophagy using ALT001 prevents mitochondrial damage caused by HSV1 through ULK1/Rab9-mediated pathway. Furthermore, ALT001-induced ULK1/Rab9-dependent mitophagy restricts HSV1 infection by activating interferon-mediated antiviral immunity. Consequently, ALT001 reduces HSV1-triggered neuroinflammation, recovers HSV1-altered microglial phagocytosis for Aβ, and efficiently reverses morphological and molecular abnormalities in HSV1-infected microglia by triggering mitophagy in ES-MG. ALT001 also suppressed HSV1-mediated Aβ accumulation and neurodegeneration in the microglia-neuron co-culture and cerebral organoid model. Conclusions: In this study, we identified a critical molecular link between HSV1 and AD-related microglial dysfunction. Furthermore, our findings provide an evidence that therapeutic targeting of alternative mitophagy via ALT001 effectively interfere with HSV1-induced microglial dysfunction and alleviate neurodegeneration.
DNA nanorobot for mitochondria-targeted microRNAs detection and tailored regulation
Authors: Ping Huang, Xiaoqi Tang, Shuang Zhao, Jie Luo, Yu Tang, Binpan Wang, Zuowei Xie, Xianlan Wu, Shuang Xie, Ming Chen, Kai Chang
Journal: Theranostics (2025)

Rationale: Mitochondrial miRNAs (mitomiRs) are crucial regulators of mitochondrial functions and play pivotal roles in tumorigenesis and cancer progression. Nevertheless, direct monitoring mitomiRs and regulating mitochondrial function at the subcellular level remains challenging. Methods: In this study, we present a versatile DNA framework-based nanorobot for synchronous ultrasensitive detection of mitochondrial miRNAs (mitomiRs) and modulation of the mitochondria-associated apoptosis process. The DNA nanorobot features a tetrahedral nucleic acid framework as its structural body, two DNA hairpins (H1 and H2) as functional arms, and a mitochondria-targeting triphenylphosphine (TPP) group as the command center. The DNA nanorobot was comprehensively characterized for its morphological properties, mitochondria-targeting capacity, mitomiRs detection performance, DOX-loading and release behaviors, and antineoplastic effects both in vitro and in vivo. Results: Upon recognizing mitomiRs, the arms of the DNA nanorobot activate and trigger spatially restricted catalytic hairpin assembly (CHA) reactions with accelerated kinetics to generate amplified fluorescence signals. Additionally, the lipophilic anticancer drug doxorubicin (DOX) encapsulated within the DNA nanorobot induces reactive oxygen species (ROS) production, leading to mitochondria damage and promoting mitochondria-associated apoptosis in tumor cells. Conclusion: This newly developed DNA nanorobot provides a multifunctional platform for precise mitochondria-targeted diagnosis and enhanced therapeutic efficacy, advancing innovative strategies for mitochondria-focused tumor diagnosis and treatment.
Activation of FANCC attenuates mitochondrial ROS-driven necroptosis by targeting TBK1-dependent mitophagy in astrocytes after spinal cord injury
Authors: Mingjie Xia, Chaochen Li, Jiajia Chen, Chunshuai Wu, Jinlong Zhang, Hongxiang Hong, Jiawei Jiang, Guanhua Xu, Zhanyang Qian, Zhiming Cui
Journal: Theranostics (2025)

Rationale: Necroptosis in astrocytes induced by mitochondrial dysfunction following spinal cord injury (SCI) significantly contributes to neuronal functional deficits. Mitophagy plays a crucial role in clearing damaged mitochondria and inhibiting necroptosis. Fanconi anemia complementation group C (FANCC), a member of the Fanconi anemia gene family, exerts a protective role by facilitating mitophagy in immune processes. However, the role of FANCC in SCI-induced astrocytic necroptosis and the underlying mechanisms remain unexplored. Methods: Astrocyte-specific FANCC conditional knockout (Fanccfl/fl-GFAP-Cre) mice, obtained by mating Fanccfl/fl mice with GFAP-Cre mice, served as a model of moderate thoracic spinal cord contusion injuries. Using bulk and single-nucleus RNA sequencing, we investigated the protective role of FANCC in astrocytes after SCI. We assessed necroptosis and mitophagy in astrocytes through quantitative PCR, western blotting, flow cytometry, immunofluorescence, and transmission electron microscopy. Molecular mechanisms were explored via co-immunoprecipitation, proteomics, molecular docking, and confocal imaging. Computer virtual screening identified poliumoside as a FANCC activator. Histopathological staining and functional assessments (gait analysis, Basso Mouse Scale, and hindlimb reflex score) were conducted to evaluate the therapeutic effects of poliumoside on SCI. Results: Astrocytic FANCC deficiency exacerbated necroptosis and mitochondrial damage, leading to severe neurological deficits. Conversely, FANCC overexpression increased PTEN-induced kinase 1-Parkin expression, thereby activating mitophagy and reducing necroptosis. Proteomics revealed FANCC's interaction with a specific peptide of TANK-binding kinase 1 (TBK1), which further promoted mitophagy. Treatment with the FANCC activator poliumoside improved neural pathology and motor function recovery in SCI mice. Conclusion: The current study indicated that FANCC interacts with TBK1 and consequently mediates Parkin translocation, activates mitophagy, and inhibits astrocyte necroptosis. Our findings demonstrate the neuroprotective role and therapeutic potential of FANCC for SCI amelioration.
RNF138 regulates skeletal muscle differentiation via the Wnt/β-catenin signaling pathway
Authors: Wenhao Wang, Zhuohua Wang, Rourong Li, Weiyi Huang, Qiao Ling, Xiaoxiao Li, Zan Li, Manqi Cao, Zhihui Zhang, Qingrong Sun, Zhijuan Liang, Hua-An Zhang, Xuan Jiang, Chuwen Lin, Yaoqing Chen, Bo Zhao, Yu Zhao, Ji-An Pan, Xiaoxue Peng
Journal: Theranostics (2025)

Rationale: Myogenesis is a strictly regulated process driven by signaling pathways activating muscle-specific gene expression. During myogenesis, muscle stem cells exhibit DNA damage response (DDR) features, which are essential for myoblast differentiation and skeletal muscle regeneration. However, the specific roles of DDR-associated proteins in these processes are not yet fully understood. Methods: Gene knockdown and knockout were used in cell and animal models to study RNF138's function in myoblast differentiation and skeletal muscle regeneration. Multi-omics profiling, including transcriptomics and proteomics, was conducted to identify the key proteins regulated by RNF138 in myogenesis. Protein turnover assays were utilized to investigate RNF138's role in APC protein turnover. Immunofluorescence microscopy was performed to confirm the protein colocalization and subcellular localization. Results: RNF138 expression increases during myoblast differentiation and in regenerating myofibers following muscle injury. Knockdown of RNF138 in C2C12 myoblasts impairs myogenic differentiation and fusion. Additionally, Rnf138-deficient mice exhibit delayed muscle regeneration following cardiotoxin-induced injury. Multi-omics profiling, including transcriptomics and proteomics, reveals that Wnt/β-catenin signaling, a key driver of myogenic differentiation, is enhanced by RNF138. Mechanistically, RNF138 stabilizes β-catenin and enhances its nuclear localization by facilitating lysosomal degradation of APC, a component of the β-catenin degradation complex responsible for mediating the export of β-catenin from the nucleus to the cytoplasm for further ubiquitin-proteasome degradation. Conclusions: We reveal a noncanonical role for RNF138, an E3 ubiquitin ligase, as a positive regulator of myoblast differentiation and skeletal muscle regeneration via the Wnt/β-catenin pathway. This finding highlights the noncanonical function of RNF138 beyond its known roles in DDR and other cellular processes. Therefore, RNF138 provides a potential link between DDR and myoblast differentiation, offering new insights into the molecular regulation of muscle regeneration.