tbuckley/cabot-search huggingface dataset:
Oxytocin modulates inhibitory balance in the prelimbic cortex to support social memory consolidation during REM sleep
Authors: Yan-Chao Liu, Yu-Chen Deng, Zi-Tao Zhu, Bo Rao, Hong-Lei Shang, Li-Ke Wang, Tao Li, Ya-Rong Wang, Jian-Zhi Wang, Qing-Ping Zhang, Yang Gao, Hai-Bo Xu
Journal: Theranostics (2025)

Rationale: The prelimbic cortex (PrL), enriched with oxytocin (OXT) receptors, plays a critical role in memory consolidation. However, the role of OXT in social memory consolidation within the PrL microcircuit remains poorly understood. Methods: To examine the role of OXT signaling in social memory consolidation, we used OXT biosensors and loss-of-function approaches, including tetanus toxin-mediated silencing of OXT neurons in the paraventricular nucleus (PVNOXT), optogenetic inhibition of the PVNOXT-PrL pathway during rapid-eye-movement (REM) sleep, and local administration of an OXT receptor antagonist in the PrL. In vivo molecular biosensors for vasoactive intestinal peptide (VIP), somatostatin, and presynaptic calcium imaging were employed to assess inhibitory signaling in the PrL microcircuit. Optogenetic activation of the PVNOXT-PrL pathway and intranasal OXT were used to evaluate resilience to chronic sleep deprivation-induced social memory deficits. Results: We identified that REM-sleep OXT release via the PVN to PrL pathway supports social memory consolidation. OXT signaling deficiency reduces the activity of VIP and parvalbumin (PV) neurons, thereby disrupting the inhibitory balance between somatic inhibition mediated by PV neurons and dendritic disinhibition mediated by VIP neurons in PrL microcircuits during REM sleep. Chronic sleep deprivation (SD) disrupts OXT release and inhibitory balance, leading to pyramidal neuron hyperactivity and social memory impairments. Notably, REM-sleep-specific activation of the PVNOXT-PrL pathway or intranasal OXT restores inhibitory balance and rescues social memory deficits in SD mice. Conclusion: Our results reveal how OXT modulates inhibitory balance in the PrL microcircuit to support social memory consolidation during REM sleep, suggesting potential therapeutic strategies for treating sleep-related memory disorders.
Targeting platinum-resistant ovarian cancer by disrupting histone and RAD51 lactylation
Authors: Chenggong Sun, Xiao Li, Qiuli Teng, Xihan Liu, Li Song, Helgi B Schiöth, Huan Wu, Xinyue Ma, Zhaoyang Zhang, Changjian Qi, Haocheng Zhang, Kun Song, Qing Zhang, Beihua Kong
Journal: Theranostics (2025)

Rationale: Ovarian cancer is a highly lethal gynecological malignancy with common platinum resistance. Lactylation is involved in multiple biological processes. Thus, we explored the role of histone and non-histone lactylation in platinum resistance, providing a potential therapeutic target to overcome platinum resistance in ovarian cancer. Methods: We utilized gene set enrichment analysis to investigate lactylation-related pathway alterations between platinum-resistant and platinum-sensitive patients from the TCGA cohort. Differential expression of H3K9la was demonstrated using Western blotting and immunohistochemistry. Progression-free and overall survival were determined using a log-rank test. Drug response to cisplatin was evaluated by CCK8, apoptosis flow cytometry, and clonogenic assays in vitro. ChIP-seq and ChIP-qPCR assays were performed to identify downstream targets of H3K9la, which was further confirmed by qRT-PCR. LC-MS/MS was conducted to identify specific lactylation sites for RAD51. Co-IP was used to reveal the interaction between GCN5 and H3K9la or RAD51la. Cell line-derived and patient-derived xenograft (PDX) models of ovarian cancer were constructed for the in vivo experiments. Results: Our study showed elevated histone lactylation, especially of H3K9la, in platinum-resistant ovarian cancer. Moreover, high H3K9la indicated platinum resistance and poor prognosis of ovarian cancer. Impairing H3K9la enhanced response to cisplatin. Mechanistically, H3K9la directly activated RAD51 and BRCA2 expression to facilitate homologous recombination (HR) repair. Furthermore, RAD51K73la enhanced HR repair and subsequently conferred cisplatin resistance. H3K9la and RAD51K73la shared the same upstream regulator, GCN5. Notably, a GCN5 inhibitor remarkably improved the tumor-killing ability of cisplatin in PDX models of ovarian cancer. Conclusions: Our study demonstrated the essential role of histone and RAD51 lactylation in HR repair and platinum resistance. It also identified a potential therapeutic strategy to overcome platinum resistance and improve prognosis in ovarian cancer.
SPEAR: CRISPR-mediated ultrasensitive, specific and rapid one-pot detection strategy for cancer-related SNPs
Authors: Linlin Bai, Yanan Pang, Ting Wang, Shengzhou Wang, Kaiming Guo, Tian Xuan, Ziqin Zhang, Dianwei Liu, Feng Qian, Yan Zheng, Gang Jin, Rui Wang
Journal: Theranostics (2025)

Rationale: The ultrasensitive and accurate detection of driver mutations is critical for early cancer screening and precision medicine. Current methods face challenges in balancing sensitivity, specificity, and speed, which limits their clinical utility. Therefore, a rapid, sensitive, and specific method is essential for detecting cancer-related SNPs. Methods: This study introduces SPEAR (Specific Point mutation Evaluation via CRISPR-Cas Assisted Recognition), a novel methodology combining NEAR (Nicking Enzyme Amplification Reaction) isothermal amplification with SNP-specific recognition by Cas12b RNP in a one-pot configuration to detect cancer-related single nucleotide polymorphisms (SNPs). SPEAR leverages the power of NEAR isothermal amplification to efficiently amplify target DNA, followed by Cas12b RNP for SNP-specific recognition. This integrated approach ensures a rapid and precise mutation detection system in a single reaction. Results: The method was applied to blood samples for the detection of cancer-related mutations, with results obtained in approximately 30 min. The SPEAR enables detection of gene mutations at the single-molecule level and it can detect targets at a 0.1% ratio despite strong background interference. The method exhibits single-base resolution specificity, allowing for the detection of multiple SNPs in a single reaction. It outperforms first-generation sequencing (FGS) in both convenience and sensitivity, while remaining compatible with next-generation sequencing (NGS). Conclusion: SPEAR offers a rapid, sensitive, and convenient approach to detect cancer-related SNPs, with significant potential for clinical applications, including real-time detection and molecular diagnostics in precision medicine.
Multiple regulatory mechanisms, functions and therapeutic potential of chaperone-mediated autophagy
Authors: Yuhan Wang, Jingwei Liu, Hao Wang, Pengcheng Jiang, Liangzi Cao, Songming Lu, Siyi Zhang, Ruohan Yang, Hao Feng, Liu Cao, Xiaoyu Song
Journal: Theranostics (2025)

Autophagy refers to the proteolytic degradation of cytoplasmic components by lysosomes, and includes three defined types: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the regulatory pathways of macroautophagy are well defined, how CMA is accurately regulated remains less understood. In recent years, emerging evidence has suggested that chaperone-mediated autophagy is regulated by multiple mechanisms at nucleic acid and protein levels. In this review, we summarized recent progress on multiple regulatory mechanisms and functions concerning CMA, as well as novel treatments targeting specific regulation sites.
Tumor-derived exosomes induce neutrophil infiltration and reprogramming to promote T-cell exhaustion in hepatocellular carcinoma
Authors: Wenchao Bi, Xue Li, Yu Jiang, Tongtong Gao, Huajun Zhao, Qiuju Han, Jian Zhang
Journal: Theranostics (2025)

Rationale: High neutrophil infiltration in hepatocellular carcinoma (HCC) is associated with a poor prognosis in patients with HCC. Tumor-derived exosomes (TDEs) have been proven to be important in the reprogramming of tumor-associated neutrophils (TANs), but the roles and mechanisms have not been fully clarified. Methods: The roles of HCC-exosome-reprogrammed neutrophils on tumor progression were evaluated in the DEN/CCl4-induced HCC mouse model by blocking neutrophil infiltration, depleting neutrophil, and neutrophil adoptive transfer. Transcriptome sequencing and flow cytometry were performed to investigate the effects of HCC exosomes on the phenotype and function of neutrophils. The mobilization and apoptosis of neutrophils were evaluated by the Transwell experiment and Annexin V/7-AAD staining, respectively. Moreover, we detected the effects of HCC-exosome-reprogrammed neutrophils on T cells by flow cytometry. Next, we used the NF-κB pathway inhibitor JSH-23 and miR-362-5p inhibitor or mimic to determine the molecular mechanisms. Lastly, we constructed the miR-362-5p sponge to validate its targeted therapeutic potential. Results: We found that HCC exosomes induced neutrophil infiltration and T-cell exhaustion in the livers of DEN/CCl4-induced HCC mice and promoted tumor progression. Blocking neutrophil infiltration and depleting neutrophils diminished these promotive effects of HCC exosomes. In addition, HCC exosome-reprogrammed neutrophils display proinflammatory and protumor phenotypes, and can directly induce T-cell exhaustion in vitro. The transfer of HCC exosome-reprogrammed neutrophils exacerbated tumor progression and induced T-cell exhaustion, as evidenced by the downregulation of IFN-γ and TNF-α, and the upregulation of PD-1 and Tim3 in T cells. Mechanistically, we found that HCC exosomes upregulate the expression of miR-362-5p in neutrophils and activate the NF-κB signaling pathway by targeting CYLD, promoting the survival and recruitment of neutrophils. In HCC mice, blocking miR-362-5p suppressed neutrophil infiltration, attenuated T-cell exhaustion, and suppressed HCC progression. Conclusions: This study clarified the roles of HCC exosomes on neutrophil infiltration and reprogramming and identified a potential target miR-362-5p for HCC treatment.
TFEB promotes Ginkgetin-induced ferroptosis via TRIM25 mediated GPX4 lysosomal degradation in EGFR wide-type lung adenocarcinoma
Authors: Hao-Jie Wang, Ling-Feng Dong, Li-Li Ding, Xiu-Yuan Miao, Yu-Wen Zhang, Li-Ping Zhao, Li-Hua Yu, Zhen-Rong Guan, Ya-Ping Jiang, Xiao-Qi Tang, Ya-Xin Yan, Jian-Shu Lou
Journal: Theranostics (2025)

Rationale: TFEB activation is associated with prolonged survival in LUAD patients, suggesting potential benefits of TFEB agonists in LUAD treatment. In this study, we identify ginkgetin (GK), derived from Ginkgo folium, as a natural TFEB agonist, which has demonstrated promising anticancer effects in our previous research. TFEB activation has been shown to promote GPX4 degradation, inducing ferroptosis; however, the specific E3 ligases, deubiquitinating enzymes (DUBs), and types of polyubiquitination chains involved remain unclear. The unique mechanisms associated with natural compounds like GK may help elucidate the underlying biological processes. Here, we describe a novel biological event involved in the lysosomal degradation of GPX4 induced by TFEB activation through the utilization of GK. Methods: TFEB activation was induced with GK, and TFEB knockout cells were generated using CRISPR-Cas9. The activity of TFEB and its relationship with ferroptosis were assessed by immunoprecipitation, labile iron pool and lysosomal activity assays. The types of polyubiquitination chains, E3 ligases, and DUBs involved in GPX4 degradation were analyzed using LC-MS, immunoprecipitation, and immunofluorescence. These findings were further validated in an orthotopic xenograft SCID mouse model. Results: GK binds to and activates TFEB, leading to TFEB-mediated lysosomal activation and GPX4 degradation, which induces ferroptosis in LUAD cells. These effects were impaired in TFEB knockout cells. Mechanistically, K48-linked polyubiquitination of GPX4 was required for GK induced GPX4 lysosomal translocation. TFEB knockout reduced both K48-linked ubiquitination and lysosomal translocation of GPX4. Additionally, GK promotes the binding of TFEB and TRIM25. TRIM25 and USP5 were found to competitively bind to GPX4, with TFEB activation favoring TRIM25 binding to GPX4 and reducing the interaction of USP5 and GPX4. These findings were confirmed in a xenograft SCID mouse model using TFEB knockout LUAD cells. Conclusion: This study identifies, for the first time, GK as a promising TFEB agonist for LUAD treatment. TFEB activation promotes TRIM25-mediated K48-linked polyubiquitination and lysosomal degradation of GPX4, driving ferroptosis. This ferroptosis-driven mechanism offers a novel strategy to enhance ferroptosis-based anti-LUAD therapies.
Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma: Erratum
Authors: Lu-Ning Qin, Heng Zhang, Qing-Qing Li, Ting Wu, Shan-Bin Cheng, Kai-Wen Wang, Yue Shi, Hao-Ran Ren, Xue-Wu Xing, Cheng Yang, Tao Sun
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.90322.].
Ironomycin induces mantle cell lymphoma cell death by targeting iron metabolism addiction
Authors: Sara Ovejero, Laura Alibert, Julie Devin, Tatiana Cañeque, Valentin Jacquier, Andrea Romero, Salome Amar, Matthieu Abouladze, Elvira Garcia de Paco, Ouissem Karmous Gadacha, Guilhem Requirand, Nicolas Robert, Miss Leriem Zellagui, Hugues de Boussac, Guillaume Cartron, Johanna Chiche, Jean-Ehrland Ricci, Charles Herbaux, Raphael Rodriguez, Jerome Moreaux, Caroline Bret
Journal: Theranostics (2025)

Rationale: Mantle-cell lymphoma (MCL) remains an aggressive and incurable cancer. Accumulating evidence reveals that abnormal iron metabolism plays an important role in tumorigenesis and in cancer progression of many tumors. Based on these data, we searched to identify alterations of iron homeostasis in MCL that could be exploited to develop novel therapeutic strategies. Methods: Analysis of the iron metabolism gene expression profile of a cohort of patients with MCL enables the identification of patients with a poor outcome who might benefit from an iron homeostasis-targeted therapy. We analyzed the therapeutic interest of ironomycin, known to sequester iron in the lysosome and to induce ferroptosis. Results: In a panel of MCL cell lines, ironomycin inhibited MCL cell growth at nanomolar concentrations compared with conventional iron chelators. Ironomycin treatment resulted in ferroptosis induction and decreased cell proliferation rate, with a reduced percentage of cells in S-phase together with Ki67 and Cyclin D1 downregulation. Ironomycin treatment induced DNA damage response, accumulation of DNA double-strand breaks, and activated the Unfolded Protein Response (UPR). We validated the therapeutic interest of ironomycin in primary MCL cells of patients. Ironomycin demonstrated a significant higher toxicity in MCL cells compared to normal cells from the microenvironment. We tested the therapeutic interest of combining ironomycin with conventional treatments used in MCL. We identified a synergistic effect when ironomycin is combined with Ibrutinib, Bruton's tyrosine kinase (BTK) inhibitor, associated with a strong inhibition of B-Cell receptor (BCR) signaling. Conclusion: Altogether, these data underline that MCL patients my benefit from targeting iron homeostasis using ironomycin alone or in combination with conventional MCL treatments.
Antigen-presenting fibroblasts: emerging players in immune modulation and therapeutic targets
Authors: Xiaoyun Chen, Fangqi Chen, Sujie Jia, Qianjin Lu, Ming Zhao
Journal: Theranostics (2025)

Antigen-presenting fibroblasts are a newly recognized subset that challenges the traditional view of these cells as mere structural components. Under pathological or environmental stimuli, fibroblasts acquire antigen-presenting capabilities through the expression of MHC-II molecules and co-stimulatory factors, enabling them to interact with T cells and modulate immune responses. These specialized fibroblasts have been identified across various tissues and diseases, where they play context-dependent roles, either amplifying immune dysregulation or contributing to immune homeostasis. This review synthesizes recent advances in understanding the origins, activation, and functions of antigen-presenting fibroblasts. It highlights their role in promoting pathogenic immune responses and offering therapeutic opportunities through targeted modulation. Advancing our understanding of antigen-presenting fibroblasts holds great promise for developing innovative approaches to immune modulation and therapy across a range of diseases.
LCN2 deficiency mitigates the neuroinflammatory damage following acute glaucoma
Authors: Tu Hu, Shuhan Meng, Can Liu, Weizhou Fang, Zhaohua Xia, Yiqun Hu, Jia Luo, Xiaobo Xia
Journal: Theranostics (2025)

Rationale: Acute high intraocular pressure (IOP) induces retinal ischemia/reperfusion (RI/R) that further initiates neuroinflammatory responses. This event can cause retinal tissue damage and neuronal death, ultimately resulting in irreversible blindness worldwide that lacks effective therapies, validated treatment targets and underlying mechanisms. We sought to explore the potential mechanisms on the causal link between the neuroinflammatory response and neurodegeneration following acute high IOP. Methods: A rat model of RI/R induced by acute high IOP was used to investigate the spatiotemporal profiles of blood-retinal barrier (BRB) disruption, peripheral immune cell infiltration, and innate immune cell response following acute glaucomatous injury. RNA sequencing and in vivo transfection with adeno-associated virus (AAV) were used to explore the pathogenic mechanisms of acute high IOP-induced neuroinflammation. Results: Disruption of the inner BRB and infiltration of macrophages and lymphocytes occurred during the early stage after acute high IOP. These events were accompanied by an innate immune response. RNA sequencing revealed that Lipocalin-2 (Lcn2) was one of the most significantly up-regulated inflammation-related genes. Lcn2 knockdown ameliorated inner BRB disruption, peripheral immune cell infiltration, and innate immune cell response, resulting in neuroprotective effects. Furthermore, we found that acute glaucomatous injury triggers high expression of LCN2 in the peripheral serum, which is strongly associated with the severity of the neuroinflammatory response in the retina. Conclusions: A "neuroinflammatory cascade" characterized by breakdown of inner BRB, peripheral immune cell infiltration, and innate immune cell response occurs during the initial stage following glaucomatous injury. We also identified a novel mechanism for LCN2 in acute high IOP-induced neuroinflammation. LCN2 has the potential to serve as a candidate biomarker for predicting the severity of the neuroinflammatory response following acute glaucoma, which may provide new evidence to retinal repair strategies for better visual function recovery at intervention time points and new targets.
CRISPR screening reveals ZNF217 as a vulnerability in high-risk B-cell acute lymphoblastic leukemia
Authors: Xi Qin, Keren Zhou, Lei Dong, Lu Yang, Wei Li, Zhenhua Chen, Chao Shen, Li Han, Yangchan Li, Anthony K N Chan, Sheela Pangeni Pokharel, Ying Qing, Meiling Chen, Kitty Wang, Keith Leung, Lillian Sau, Chun-Wei Chen, Xiaolan Deng, Rui Su, Jianjun Chen
Journal: Theranostics (2025)

Rationale: Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate. Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%. The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses. This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL. Methods: The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth. Both in vitro and in vivo models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL. To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation. Results: Through the focused CRISPR-Cas9 screening, ZNF217 emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL. Through in vitro gain- and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth. Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that ZNF217 depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice. Through integrative multiple-omics analysis, we elucidated that ZNF217 exerts its oncogenic role in B-ALL through both CoREST-dependent and CoREST-independent mechanisms. Furthermore, we characterized FOS as a functionally essential downstream target of ZNF217, and ZNF217 inhibited FOS expression in a CoREST-independent manner. Conclusions: Our findings highlight ZNF217 as a promising therapeutic target for the treatment of high-risk B-ALL, such as those carrying MLL-rearrangements or BCR-ABL fusion.
Glioblastoma progression is hindered by melatonin-primed mesenchymal stromal cells through dynamic intracellular and extracellular reorganizations
Authors: Laura Olmedo-Moreno, Concepción Panadero-Morón, Jesús María Sierra-Párraga, Rubén Bueno-Fernández, Emily S Norton, Yolanda Aguilera, Nuria Mellado-Damas, Patricia García-Tárraga, Raquel Morales-Gallel, María Antequera-Martínez, Raúl V Durán, Jaime Ferrer-Lozano, Germaine Escames, José Manuel García-Verdugo, Alejandro Martin-Montalvo, Hugo Guerrero-Cázares, Vivian Capilla-González
Journal: Theranostics (2025)

Rationale: Glioblastoma (GBM) is the most fatal form of brain cancer and its treatment represents a persistent challenge. Mesenchymal stromal cells (MSCs) have been explored as therapeutic tools in cancer management owing to their tumor-homing abilities. However, their clinical application is limited due to the controversial role of MSCs in carcinogenesis. This study investigates how MSCs influence tumor behavior and explores the synergistic anticancer effects in combination with melatonin (Mel). Methods: Orthotopic and subcutaneous GBM xenograft mouse models were used to assess the antitumor effect of Mel pre-treated MSCs (MSCMel). Histological, immunohistochemical, and ultrastructural analyses were conducted to identify phenotypic changes in tumors. Through a set of in vitro assays, including direct and indirect co-cultures, dynamic single-cell tracking and tumorsphere assay, we explored the impact of MSCMel on primary and non-primary GBM cells. Transcriptomic profiling was used to identify genes and pathways modulated by this synergistic therapy. Results: MSCMel delayed tumor growth in mice and increased collagen deposition. Additionally, MSCMel showed enhanced capacity to prevent GBM cell migration compared to untreated MSCs. Molecular analysis identified genes and proteins related to cell migration, cytoskeletal dynamics and extracellular matrix remodeling in GBM cells exposed to MSCMel, including reduced vimentin expression. Finally, a genetic signature associated with the clinical outcomes of GBM patients was identified. Conclusions: Our study demonstrates that melatonin enhances the anticancer properties of MSCs, providing new insights into their interaction with GBM cells and tumor environment. These findings offer valuable guidance for advancing MSC-based therapies in clinical practice.