Neoplasia最新文献

{"title":"Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas","authors":"Mengqian Huang ,&nbsp;Zhuang Kang ,&nbsp;Shenglan Li ,&nbsp;Botao Zhang ,&nbsp;Yantao Xiao ,&nbsp;Shangwei Li ,&nbsp;Wenbin Li","doi":"10.1016/j.neo.2025.101141","DOIUrl":"10.1016/j.neo.2025.101141","url":null,"abstract":"<div><h3>Objective</h3><div>Despite a standard of care, the mortality of recurrent high-grade gliomas (HGGs) remains high. SM-1 is a novel molecular activator that has shown to target procaspase-3, which is overexpressed in HGGs. A phase I clinical trial was conducted to evaluate the safety, pharmacokinetics, and primary clinical efficacy of SM-1 plus TMZ. Participants received escalating doses of daily oral SM-1 (450, 600, and 800 mg) plus standard TMZ therapy.</div></div><div><h3>Methods</h3><div>In the preclinical study, the synergistic effects of SM-1 and temozolomide (TMZ) in rodent models were evaluated. In the clinical study, adult patients received SM-1 therapy in various doses in combination with a standard TMZ dosing. The tolerability and pharmacokinetics data of the combination therapy were tested. The primary efficacy was measured by tumor response in accordance with the RANO criteria.</div></div><div><h3>Results</h3><div>A total of 13 patients with recurrent HGG were enrolled, with 11 patients completed ≥ two cycles of therapy and received tumor assessment. Among them, one patient had complete response, whereas two patients had partial response for the best change from baseline. No dose-limited toxicities were observed, and no maximum tolerated dose was reached.</div></div><div><h3>Conclusion</h3><div>SM-1 has the potential to enhance antitumor activity while alleviating the side effects of TMZ. SM-1 exhibited mild toxicity in patients with recurrent HGG. The combination of SM-1 and TMZ warrants further investigation, with promising clinical outcomes. The monotherapy phase and expansion phase of SM-1 are still ongoing. (ClinicalTrials.gov number, CTR20221641).</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101141"},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of 68 HLA-A24 and -A2-restricted cytotoxic T lymphocyte-inducing peptides derived from 10 common cancer-specific antigens frequently expressed in various solid cancers","authors":"Hiroki Kinoshita ,&nbsp;Kazumasa Takenouchi ,&nbsp;Nobuo Tsukamoto ,&nbsp;Kazunobu Ohnuki ,&nbsp;Toshihiro Suzuki ,&nbsp;Tetsuya Nakatsura","doi":"10.1016/j.neo.2025.101135","DOIUrl":"10.1016/j.neo.2025.101135","url":null,"abstract":"<div><div>Targeting cancer antigens expressed in cancer cells is necessary to develop cancer-specific immunotherapy. We have performed immunohistochemical analysis of various solid cancer specimens, adding ROBO1, AFP, TGFBI, EphB4, CLDN1, and LAT1 to the previously studied glypican-3 (GPC3), HSP105α, FOXM1, and SPARC, and found that these 10 common cancer antigens are sufficient to cover most solid cancers. These antigens were frequently expressed in various solid cancers but shown to be rarely ex-pressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. In this study, we predicted 72 and 73 peptides that bind to HLA-A24 and -A2 <em>in silico</em> from the full-length amino acid sequences of these 10 common cancer antigens and immunized each HLA transgenic mouse with a cocktail of synthesized peptides together with the poly I:CLC three times weekly to analyze the antigen-specific immune response. As a result, 68 peptide sequences (30 and 38, respectively) were identified that had higher cytotoxic T lymphocyte (CTL) induction ability than GPC3 298-306 and GPC3 144-152 used in the clinical trials. Furthermore, experiments with cocktail peptide vaccines using mouse models expressing subcutaneous tumors of each antigen showed promising results in terms of safety and efficacy. These peptides identified in this study, derived from 10 common cancer antigens covering all solid cancers, are expected to be clinically applicable as cocktail peptide vaccines.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101135"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability","authors":"James Ephraums ,&nbsp;Janet Youkhana ,&nbsp;Aparna S. Raina ,&nbsp;Grace Schulstad ,&nbsp;Kento Croft ,&nbsp;Amanda Mawson ,&nbsp;John Kokkinos ,&nbsp;Estrella Gonzales-Aloy ,&nbsp;Rosa Mistica C. Ignacio ,&nbsp;Joshua A. McCarroll ,&nbsp;Cyrille Boyer ,&nbsp;David Goldstein ,&nbsp;Marina Pajic ,&nbsp;Koroush S. Haghighi ,&nbsp;Amber Johns ,&nbsp;Anthony J. Gill ,&nbsp;Mert Erkan ,&nbsp;Australian Pancreatic Cancer Genome Initiative (APGI) ,&nbsp;Phoebe A. Phillips ,&nbsp;George Sharbeen","doi":"10.1016/j.neo.2025.101138","DOIUrl":"10.1016/j.neo.2025.101138","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101138"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export","authors":"Hoon Choi ,&nbsp;Mamta Gupta ,&nbsp;Arjun Sengupta ,&nbsp;Emma E. Furth ,&nbsp;Christopher Hensley ,&nbsp;Aalim M. Weljie ,&nbsp;Hsiaoju Lee ,&nbsp;Yu-Ting Lu ,&nbsp;Austin Pantel ,&nbsp;David Mankoff ,&nbsp;Rong Zhou","doi":"10.1016/j.neo.2025.101136","DOIUrl":"10.1016/j.neo.2025.101136","url":null,"abstract":"<div><div>Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant <em>in vitro</em> and their xenograft models <em>in vivo</em>. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101136"},"PeriodicalIF":4.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT signaling in the pathogenesis and therapy of acute myeloid leukemia and myelodysplastic syndromes","authors":"Zoe King ,&nbsp;Sudhamsh Reddy Desai ,&nbsp;David A. Frank ,&nbsp;Aditi Shastri","doi":"10.1016/j.neo.2025.101137","DOIUrl":"10.1016/j.neo.2025.101137","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent complex hematopoietic malignancies characterized by ineffective hematopoiesis and dysregulated myeloid differentiation. Recent research has underscored the critical role of aberrant STAT signaling pathways, particularly involving STAT3 and STAT5, in the pathogenesis of these disorders. Aberrant activation of STAT proteins has been implicated as a mediator of oncogenesis in several malignancies. In this review, we discuss the role of STAT proteins in both regulated and dysregulated hematopoiesis, the consequences of dysregulation in acute myeloid leukemia and myelodysplastic syndromes, therapeutic strategies, and recent advancements in STAT-targeted therapy. By integrating findings from recent preclinical and clinical studies, this review provides insights into the evolving landscape of STAT-targeted therapies, highlighting the promise of these approaches in enhancing treatment efficacy and improving patient outcomes in high-risk hematologic malignancies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101137"},"PeriodicalIF":4.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer stem-like cells stay in a plastic state ready for tumor evolution","authors":"Jiali Xu ,&nbsp;Houde Zhang ,&nbsp;Zhihao Nie ,&nbsp;Wenyou He ,&nbsp;Yichao Zhao ,&nbsp;Zhenhui Huang ,&nbsp;Lin Jia ,&nbsp;Zhiye Du ,&nbsp;Baotong Zhang ,&nbsp;Siyuan Xia","doi":"10.1016/j.neo.2025.101134","DOIUrl":"10.1016/j.neo.2025.101134","url":null,"abstract":"<div><div>Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101134"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143267549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Atorvastatin on Intraprostatic Biomarkers – Prognostic Value of 3LS-score – Follow-up of ESTO1-Trial","authors":"Eemil Lehtonen ,&nbsp;Maiju Vertanen ,&nbsp;Heimo Syvälä ,&nbsp;Teemu Tolonen ,&nbsp;Seppo Auriola ,&nbsp;Teuvo Tammela ,&nbsp;Aino Siltari ,&nbsp;Teemu Murtola","doi":"10.1016/j.neo.2025.101132","DOIUrl":"10.1016/j.neo.2025.101132","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) remains a global health burden, with limited reliable biomarkers beyond prostate-specific antigen (PSA). Statins have been associated with survival benefits in advanced Pca, potentially by modulating cholesterol metabolism and tumor biology. However, the causal mechanisms are not well understood. A distinct three-lipid signature (3LS) has previously been proposed as a prognostic biomarker for PCa.</div></div><div><h3>Objective</h3><div>This study investigates the effects of atorvastatin intervention on PCa tissue markers, long-term clinical outcomes, and the prognostic value of the 3LS derived from prostate tissue lipidome.</div></div><div><h3>Methods</h3><div>The ESTO1 trial randomized 158 statin-naïve PCa patients to receive high-dose atorvastatin (80 mg daily) or placebo before prostatectomy. Long term outcomes were assessed for 102 patients through medical records review. Prostate tissue samples were pathologically characterized, and lipidome quantified. Cox regression models were used to analyse clinical outcomes between the groups. The 3LS score was calculated by identifying the constituent lipids from the prostate lipidome.</div></div><div><h3>Findings</h3><div>Higher intraprostatic atorvastatin lactone concentrations were associated with reduced Ki67 expression and PSA levels. After a median follow-up of seven years, no significant differences were observed in biochemical recurrence, overall mortality, or initiation of hormonal therapy. However, the atorvastatin arm had a lower risk of major acute cardiovascular events (HR 0.11, 95% CI 0.01–1.01). The intraprostatic 3LS correlated with higher baseline tumor aggressiveness but did not predict subsequent outcomes.</div></div><div><h3>Conclusion</h3><div>Higher atorvastatin lactone concentrations in the prostate tissue were linked to improved pathological variables. Pre-surgery statin intervention reduced MACE risk but no impact on other clinical outcomes was observed. The 3LS from prostate tissue does not seem to be prognostic marker in localized Pca.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101132"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143268468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma","authors":"Aránzazu Chamorro-Jorganes ,&nbsp;Núria Profitós-Pelejà ,&nbsp;Clara Recasens-Zorzo ,&nbsp;Juan G Valero ,&nbsp;Diana Reyes-Garau ,&nbsp;Laura Magnano ,&nbsp;Ray Butler ,&nbsp;Antonio Postigo ,&nbsp;Patricia Pérez-Galán ,&nbsp;Marcelo Lima Ribeiro ,&nbsp;Gaël Roué","doi":"10.1016/j.neo.2025.101131","DOIUrl":"10.1016/j.neo.2025.101131","url":null,"abstract":"<div><div>A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) cases harbor a gain-of-function, heterozygous somatic mutation of the methyltransferase gene EZH2. While this factor is known to cooperate with the proto-oncogene MYC during malignant B cell development, the effect of interfering with both factors remains underexplored. Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of <em>MYC</em> transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. We observed a specific and synergistic antiproliferative effect of these compounds in EZH2-mutated cells and mouse xenograft models, that was related to the abrogation of MYC transcriptional program and to tumor cell proliferation blockade at the G1 cell cycle phase. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both <em>in vitro</em> and <em>in vivo</em>. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101131"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143129964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An open-label study to determine the maximum tolerated dose of oral ESK-440 administered as a single agent in patients with advanced or metastatic solid tumors","authors":"Russell J. Schilder ,&nbsp;Drew Rasco ,&nbsp;Manish R. Sharma","doi":"10.1016/j.neo.2025.101133","DOIUrl":"10.1016/j.neo.2025.101133","url":null,"abstract":"<div><h3>Purpose</h3><div>Anaplastic lymphoma kinase (ALK) dysregulation is implicated in numerous cancers. Tyrosine kinase inhibitors (TKIs) targeting ALK have improved disease outcomes, but resistance mechanisms are common. This first-in-human trial evaluates ESK-440, a dual inhibitor of ALK and focal adhesion kinase, as a novel strategy for cancers with resistance to ALK-targeting TKIs.</div></div><div><h3>Methods</h3><div>This phase 1, open-label, dose-finding study evaluated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics of ESK-440 in participants with advanced or metastatic solid tumors (ClinicalTrials.gov: NCT01922752). A 3 + 3 dose-escalation design, with daily doses ranging from 25 to 700 mg/day of ESK-440 for each 28-day treatment cycle (6 to 8 cycles) was utilized to identify the MTD. A phase 1b was planned to further evaluate ESK-440 safety and antitumor activity at the MTD but was not performed due to sponsor decision.</div></div><div><h3>Results</h3><div>32 participants were enrolled and 24 (75 %) completed cycle 1 of treatment. Three dose-limiting toxicities, all grade 3 nausea, were reported (<em>n</em> = 1, 500 mg; <em>n</em> = 2, 700 mg). The MTD was determined to be 500 mg daily. The most frequent adverse events (AEs) were fatigue and nausea (53 % each) and vomiting (38 %). Seven participants (22 %) withdrew from treatment due to AEs and 4 deaths occurred, none related to ESK-440. No participant had a complete or partial response; the best overall response was stable disease in 7 participants.</div></div><div><h3>Conclusions</h3><div><strong>ESK-440 was safe and tolerable with a maximum tolerated dose of 500</strong> <strong>mg daily</strong>; however, the study was terminated early based on sponsor decision.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101133"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143267550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZC3H15 suppression ameliorates bone cancer pain through inhibiting neuronal oxidative stress and microglial inflammation","authors":"Li-Quan Huang ,&nbsp;Ting-Xuan Yan ,&nbsp;Bao-Sheng Wang,&nbsp;Hao Li,&nbsp;Nai-Bao Zhou","doi":"10.1016/j.neo.2025.101123","DOIUrl":"10.1016/j.neo.2025.101123","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Patients with advanced-stage malignancies often endure unbearable pain, partly due to the incomplete understanding of its molecular mechanisms. Zinc finger CCCH-type containing 15 (ZC3H15) is a highly conserved eukaryotic protein involved in various cellular processes, including tumor growth and inflammation. However, its impact on cancer-induced pain, especially the underlying mechanisms, remains largely unknown.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;To evaluate the expression of ZC3H15 in cancer-induced pain, we used microcomputed tomography (MicroCT), immunoblotting, co-immunoprecipitation (Co-IP), behavior tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation. Additionally, we used CCK8, cloning, and migration tests to examine the proliferation and migration of cancer cells. We also used transplantation tumor mouse model to investigate the course of the cancer cell growth. Finally, we looked into the biological processes linked to ZC3H15 using in vivo and in vitro ubiquitination detection, which was later verified.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In this study, we established a bone cancer pain (BCP) murine mouse model that impairs patients’ quality of life. Initially, we observed a significant increase in the expression of ZC3H15 in dorsal horn spinal cord tissues of BCP mice, along with severe oxidative stress and inflammation. Subsequently, we found that adeno-associated virus (AAV) expressing ZC3H15 short hairpin RNA (shRNA) (AAV-shZC3H15) to silence ZC3H15 in vivo significantly alleviated the progression of BCP in mice, improving nociceptive behaviors, independent of tumor burden and bone destruction. Subsequently, we made a novel discovery that ZC3H15 knockdown mice with BCP displayed improved neuronal oxidative stress and reactive oxygen species (ROS) generation in spinal cord tissues, which was confirmed in H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;-treated mouse spinal cord neurons primarily through mediating the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor, erythroid 2-like transcription factor 2 (NRF2) pathway. Mechanistically, immunoblotting analysis revealed that ZC3H15 could maintain KEAP1 stability and thereby promote NRF2 ubiquitination and degradation under oxidative stress. Furthermore, the suppression of oxidative damage in neurons by ZC3H15 knockdown was significantly abolished upon the deletion of NRF2 expression, identifying the necessity of NRF2 for ZC3H15 in the mediation of BCP progression. Additionally, microglial activation and inflammatory response in spinal cord tissues of BCP mice were also attenuated by AAV-shZC3H15, which was verified in LPS-treated microglial cells &lt;em&gt;in vitro&lt;/em&gt; by blocking the inhibitory protein κBα (IκBα)/nuclear factor κB (NF-κB) signaling pathway.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our results provide evidence that suppressing ZC3H15 can alleviate BCP by restricting neuronal oxidative ","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101123"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143129963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}