Cellular & Molecular Biology Letters最新文献

{"title":"Molecular signatures of disulfidptosis: interplay with programmed cell death pathways and therapeutic implications in oncology.","authors":"Yingchao Liu, Sainan Li, Yunyi Wu, Ping Zhang, Yanhua Yu, Xi Chen, Lingyan Yu, Xinyi Yang, Huanjuan Li, Cuiyun Wu, Jing Du, Yanchun Li","doi":"10.1186/s11658-025-00743-5","DOIUrl":"10.1186/s11658-025-00743-5","url":null,"abstract":"<p><p>Disulfidptosis represents a newly identified form of regulated cell death (RCD) distinct from other well-established RCD pathways. It occurs during periods of glucose starvation, specifically when intracellular NADPH is rapidly depleted and the expression of Solute Carrier Family 7 Member 11 (SLC7A11) is highly upregulated. Cancer cells utilize SLC7A11 to import cystine from the extracellular environment, and subsequently employ NADPH to convert it into cysteine. In the event of NADPH deficiency or an impairment in its utilization, cystine accumulates within the cells. This accumulation results in abnormal disulfide bond formation within actin cytoskeleton proteins, which in turn causes the collapse of the actin network and ultimately triggers disulfidptosis. This process uncovers a metabolic vulnerability within tumors, offering novel perspectives on the mechanisms that underlie cell death. In this paper, we provide a comprehensive review of the mechanism of disulfidptosis and compare its similarities and differences with other common programmed cell death mechanisms, such as apoptosis, autophagy, ferroptosis, and cuproptosis. The aim is to gain a more profound understanding of the characteristics and mechanisms of various cell death pathways. Understanding the correlation between disulfidptosis and tumors constitutes a crucial theoretical foundation for future research endeavors in cancer treatment. This review offers valuable insights that could pave the way for developing novel cancer treatment strategies and lead to groundbreaking advancements in cancer therapy.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"66"},"PeriodicalIF":9.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FNDC3B promotes gastric cancer metastasis via interacting with FAM83H and preventing its proteasomal degradation.","authors":"Yuying Zhang, Lingyu Ran, Yuying Liu, Wei Li, Ai Ran, Haiping Li, Bo Huang, Junwu Ren, Hao Ning, Qiang Ma, Xiaolin Wang, Feifei Yang, Xiaojuan Pan, Ce Liang, Shimin Wang, Changhong Qin, Yan Jiang, Kun Qian, Bin Xiao","doi":"10.1186/s11658-025-00741-7","DOIUrl":"10.1186/s11658-025-00741-7","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is one of the most prevalent digestive tract malignancies, with metastasis being a major contributor to poor prognosis in patients. Fibronectin type III domain-containing 3B (FNDC3B) plays pivotal roles in various tumors, yet its role in GC remains unknown.</p><p><strong>Methods: </strong>We utilized a GC immunohistochemistry (IHC) chip and specimens to identify high expression of FNDC3B in GC. In vitro cellular experiments and in vivo nude mouse models were constructed to validate the biological functions of FNDC3B. Truncated mutants of FNDC3B and immunofluorescence (IF) assays were conducted to explore the critical domains of FNDC3B. Liquid chromatography-tandem mass spectrometry (LC-MS) and coimmunoprecipitation (Co-IP) were employed to screen and identify target proteins interacting with FNDC3B. Rescue experiments were performed to uncover interactions between FNDC3B and the binding protein.</p><p><strong>Results: </strong>FNDC3B was found to function as an oncogene in GC. Clinically, FNDC3B was significantly upregulated in GC specimens and associated with poor survival in patients with GC. Functionally, elevated FNDC3B promoted GC metastasis both in vitro and in vivo. Structurally, the proline-rich N-terminus and a transmembrane (TM) domain at the C-terminus were crucial for maintaining the metastasis function of FNDC3B. Mechanistically, FNDC3B interacted with FAM83H, inhibiting the ubiquitin-proteasome degradation of FAM83H, which in turn enhanced GC progression through the FNDC3B/FAM83H/Snail/EMT axis.</p><p><strong>Conclusions: </strong>Our results demonstrate that FNDC3B promotes GC metastasis and has the potential to serve as a therapeutic target for GC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"65"},"PeriodicalIF":9.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP1 promoter-associated noncoding RNA affects Ewing sarcoma cell tumorigenicity by regulating YAP1 expression.","authors":"Lidia Chellini, Arianna Del Verme, Veronica Riccioni, Maria Paola Paronetto","doi":"10.1186/s11658-025-00736-4","DOIUrl":"10.1186/s11658-025-00736-4","url":null,"abstract":"<p><strong>Background: </strong>Ewing sarcomas (ESs) are aggressive paediatric tumours of bone and soft tissues afflicting children and adolescents. Despite current therapies having improved the 5-year survival rate to 70% in patients with localized disease, 25% of patients relapse and most have metastasis at diagnosis. Resistance to chemotherapy, together with the high propensity to metastasize, remain the main causes of treatment failure. Thus, identifying novel targets for alternative therapeutic approaches is urgently needed.</p><p><strong>Methods: </strong>Biochemical and functional analyses were carried out to elucidate the mechanism of regulation of YAP1 expression by pncRNA_YAP1-1 in ES cells.</p><p><strong>Results: </strong>Here, we identified a novel promoter-associated noncoding RNA, pncRNA_YAP1-1, transcribed from the YAP1 promoter in ES cells. We found that pncRNA_YAP1-1 level exerts antitumour effects on ES by destabilizing YAP1 protein. The molecular mechanism relies on the interaction of pncRNA_YAP1-1 with the RNA binding protein FUS, which stabilizes the transcript. Furthermore, pncRNA_YAP1-1 binding to TEAD impairs its interaction with YAP1, thus determining YAP1 translocation into the cytoplasm, its phosphorylation and degradation.</p><p><strong>Conclusions: </strong>Overall, our findings reveal a novel layer of regulation of YAP1 protein expression by pncRNA_YAP1-1 in Ewing sarcoma. Considering the role of YAP1 in therapy response and cell propensity to metastasize, our results indicate pncRNA_YAP1-1 as an actionable target that could be exploited to enhance chemotherapy efficacy in Ewing sarcoma.</p><p><strong>Significance: </strong>PncRNA_YAP1-1 counteracts the YAP1 oncogenic transcriptional program in Ewing sarcoma cells by interfering with YAP1-TEAD interaction and impairing YAP1 protein stability. These findings uncover a novel treatment option for Ewing sarcoma.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"63"},"PeriodicalIF":9.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-196b strictly regulates and reliably predicts the response to cetuximab in colorectal cancer.","authors":"Shiyun Chen, Zhaoli Tan, Yanli Lin, Fang Pang, Xiaojie Wu, Xiang Li, Yumeng Cui, Weiling Man, Ying Li, Yanghua Li, Lu Han, Miaomiao Gou, Zhikuan Wang, Guanghai Dai, Youliang Wang","doi":"10.1186/s11658-025-00740-8","DOIUrl":"10.1186/s11658-025-00740-8","url":null,"abstract":"<p><strong>Background: </strong>Cetuximab resistance severely restricts its effectiveness in the treatment of patients with metastatic colorectal cancer (CRC). Previous studies have predominantly focused on the genetic level, with scant attention to the nongenetic aspects. This study aimed to identify the crucial microRNA (miRNA) that is responsible for cetuximab resistance.</p><p><strong>Methods: </strong>Key miRNAs were identified using small RNA sequencing analysis. miR-196b's role and mechanism in cetuximab resistance was explored by in vitro and in vivo experiments. Clinical blood samples were dynamically analyzed using droplet digital polymerase chain reaction (PCR) to assess the predictive value of miR-196b for efficacy.</p><p><strong>Results: </strong>We initially discovered that the extracellular signal-regulated kinase (ERK) signaling pathway was progressively activated during the acquisition of cetuximab resistance in CRC cells. Further study determined that miR-196b can inhibit the activity of ERK and protein kinase B (AKT) signaling pathways by downregulating both NRAS and BRAF, which can kill two birds with one stone, thus enhancing the sensitivity of colorectal cancer cells to cetuximab. The expression of miR-196b was found to be significantly downregulated in both cetuximab-resistant cells and the tumor tissues of patients exhibiting resistance. In the presence of cetuximab, overexpression of miR-196b further inhibited the proliferation and migration and promoted the apoptosis of CRC cells, while miR-196b silencing had the opposite effects. Importantly, analysis of clinical blood samples confirmed that miR-196b can serve as a predictive and dynamic biomarker for monitoring the outcomes of patients with CRC treated with cetuximab.</p><p><strong>Conclusions: </strong>This study supports that activation of the ERK signaling pathway is a key factor in cetuximab resistance. In addition, miR-196b can modulate and predict the CRC response to cetuximab, holding broad potential applications.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"64"},"PeriodicalIF":9.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel tRNA-derived fragment, tiRNA-Met, inhibits the malignant progression of triple-negative breast cancer by regulating RANBP3L via a targeted interaction with SNRPA.","authors":"Jingjing Lu, Yangbai Sun, Xiufen Zhang, Bujie Xu, Ping Zhu, Linzi Zeng, Xue Wang, Wei Zhu, Ping Zhou","doi":"10.1186/s11658-025-00738-2","DOIUrl":"10.1186/s11658-025-00738-2","url":null,"abstract":"<p><strong>Background: </strong>tRNA-derived fragments (tRFs) have emerged as significant noncoding RNAs in cancer biology; however, their roles and mechanisms in triple-negative breast cancer (TNBC) remain inadequately characterized.</p><p><strong>Methods: </strong>tRF and tiRNA sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization (FISH), and subcellular fractionation were used to explore the expression and characteristic of tiRNA-Met in TNBC. The biological functions of tiRNA-Met were assessed using CCK-8 assays, colony formation assays, and Transwell assays in vitro, alongside mouse xenograft models in vivo. RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), western blot, ubiquitination assays, RNA sequencing, actinomycin D assays, immunofluorescence, immunohistochemical staining, and rescue experiments were performed to explore the regulatory mechanisms of tiRNA-Met in TNBC.</p><p><strong>Results: </strong>tiRNA-Met was an uncharacterized tRF that originated from mitochondrial tRNA^Met-CAT and was primarily localized in the cytoplasm. Its expression was significantly downregulated in TNBC tumor tissues compared with adjacent normal tissues. Overexpression of tiRNA-Met markedly inhibited the proliferation, migration, and invasion of TNBC cells; whereas, its reduced expression elicited opposite effects. In addition, tiRNA-Met overexpression suppressed TNBC cell growth in vivo. Mechanistically, tiRNA-Met directly interacted with the RNA recognition motif 2 (RRM2) domain of small nuclear ribonucleoprotein A (SNRPA), promoting SNRPA protein degradation via the ubiquitin/proteasome pathway. This interaction enhanced the stability of Ran-binding protein 3-like (RANBP3L) mRNA, resulting in increased RANBP3L expression and subsequent inhibition of the mTORC1/RPS6 signaling pathway.</p><p><strong>Conclusions: </strong>Our study identified tiRNA-Met as a novel anti-oncogenic tRF and elucidated its mechanism for inhibiting the malignancy of TNBC. tiRNA-Met directly bound to SNRPA, promoting its degradation and stabilizing RANBP3L mRNA, ultimately leading to the inhibition of the mTORC1 signaling pathway. These findings position tiRNA-Met as a promising candidate for diagnostic and therapeutic applications in TNBC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"62"},"PeriodicalIF":9.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6-induced long noncoding RNA MIR3142HG promotes tumorigenesis by interacting with thioredoxin-1 and STAT3 in human colorectal cancer.","authors":"Daoquan Fang, Qian Feng, Baojian Zhou, Yangyang Liu, Yichu Lian, Yihui Zhang, Dichen Yang, Xintong Liu, Xiaomeng Shi, Wuhua Ni, Lei Jiang","doi":"10.1186/s11658-025-00742-6","DOIUrl":"10.1186/s11658-025-00742-6","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a prevalent and highly malignant neoplasm on a global scale, ranking as the second most widespread cause of cancer-associated death. Long noncoding RNAs (lncRNAs) control tumorigenic processes in CRC by modulating inflammatory signals. However, the precise mechanisms remain unknown.</p><p><strong>Methods: </strong>LncRNAs regulated by thioredoxin-1 (Trx-1) and interleukin (IL)-6 were identified by RNA sequencing (RNA-seq). The effect of MIR3142HG on CRC growth, migration, and invasion was assessed through methods of cell counting kit-8 (CCK-8), colony formation assay, Transwell assay, and animal experimentation, respectively. The regulation of signal transducer and activator of transcription 3 (STAT3) on the MIR3142HG promoter was verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The interaction of MIR3142HG with Trx-1 and STAT3 proteins was validated with RNA-binding protein immunoprecipitation (RIP) and RNA-pulldown experiments. Bioinformatics analysis and tissue microarray were utilized for evaluating the clinical value of MIR3142HG in CRC.</p><p><strong>Results: </strong>We identified a lncRNA, MIR3142HG, regulated by Trx-1 knockdown and IL-6 treatment. Overexpression of MIR3142HG enhanced CRC cell proliferation, migration, and invasion, while its knockdown impaired these processes. STAT3 bound to the MIR3142HG promoter and activated its transcription. Upregulated MIR3142HG acted as a scaffold for the Trx-1/STAT3 complex to inhibit the degradation of Trx-1 and phosphorylated STAT3 (p-STAT3). In situ hybridization (ISH) results of CRC tissues indicated that MIR3142HG expression was significantly elevated during the early stages of CRC. Moreover, consistent with the Cancer Genome Atlas (TCGA) dataset, high MIR3142HG expression predicted better survival.</p><p><strong>Conclusions: </strong>Our study identified a novel lncRNA MIR3142HG, which interacts with STAT3 and Trx-1 to promote CRC progression, providing a possible diagnostic target for CRC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"61"},"PeriodicalIF":9.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA dioxygenase TET2 deficiency aggravates sepsis-induced acute lung injury by targeting ITGA10 via the PI3K/AKT signaling pathway.","authors":"Hongxue Fu, Bin Gao, Xin Zhou, Yingting Hao, Chang Liu, Ailin Lan, Jingyi Tang, Fachun Zhou","doi":"10.1186/s11658-025-00739-1","DOIUrl":"10.1186/s11658-025-00739-1","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-induced acute lung injury (ALI) is a clinical condition with high morbidity and mortality, and impaired endothelial function is the main pathological characteristic. As a member of DNA demethylases, ten-eleven translocation protein 2 (TET2) is involved in a variety of biological processes. However, the role of TET2 in endothelial dysfunction of sepsis-induced ALI remains unclear.</p><p><strong>Methods: </strong>We used cecal ligation and puncture (CLP) to establish a sepsis-induced acute lung injury mouse model and screened out Tet2 from TET family proteins. The results suggested that Tet2 was obviously declined. We used lipopolysaccharide (LPS) to stimulate human pulmonary microvascular endothelial cells (HPMECs) as an in vitro model, and we found the expression of TET2 was also decreased. Then we used small interfering RNAs and adenovirus to knockdown or overexpress TET2 to investigate the effect of TET2 on the function of HPMECs. The changes in sepsis-induced ALI symptoms were also analyzed in Tet2-deficient mice generated by adeno-associated virus 6 (AAV6). Next, RNA sequencing and KEGG analysis were used to find the TET2-regulated downstream target genes and signaling pathways under LPS stimulation. Finally, the rescue experiments were performed to analyze the role of target genes and signaling pathways modulated by TET2 in LPS-treated HPMECs.</p><p><strong>Results: </strong>TET2 and 5-hmC levels were significantly decreased in both in vitro and in vivo models of sepsis-induced ALI. TET2 knockdown exacerbated the dysfunction and apoptosis of HPMECs induced by LPS. Conversely, TET2 overexpression significantly alleviated these dysfunctions and reduced apoptosis. Meanwhile, the lung injury of Tet2-deficient mice was aggravated by increased inflammation and apoptosis. RNA sequencing and subsequent experiments showed that TET2 overexpression could increase the expression of Integrin α10 (ITGA10) by reducing the methylation level of ITGA10 promoter. This, in turn, activated the PI3K-AKT signaling pathway. Knocking down ITGA10 weakened the beneficial effects of TET2 overexpression in LPS-stimulated endothelial cells.</p><p><strong>Conclusions: </strong>In our study, we demonstrated that TET2 deficiency aggravates endothelial cell dysfunction and promotes acute lung injury by targeting ITGA10 via the PI3K-AKT pathway. These findings indicate that TET2 may be a promising therapeutic target for treating sepsis-induced ALI.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"60"},"PeriodicalIF":9.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Narciclasine enhances cisplatin-induced apoptotic cell death by inducing unfolded protein response-mediated regulation of NOXA and MCL1.","authors":"Ji Hae Lee, Seung Hee Seo, Jaegal Shim, Yong-Nyun Kim, Kyungsil Yoon","doi":"10.1186/s11658-025-00735-5","DOIUrl":"https://doi.org/10.1186/s11658-025-00735-5","url":null,"abstract":"<p><strong>Background: </strong>Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC); however, innate and acquired resistance is clinically seen in many patients. Hence, a combinatorial approach with novel therapeutic agents to overcome chemoresistance is a promising option for improving patient outcomes. We investigated the combinational anticancer efficacy of cisplatin and narciclasine in three-dimensional NSCLC tumor spheroids.</p><p><strong>Methods: </strong>To assess the efficacy of cisplatin and narciclasine, cell viability assays, live/dead cell staining, cell death enzyme-linked immunosorbent assay (ELISA), western blot analysis for proteins related to apoptosis, and in vivo xenograft experiments were performed. The synergistic effects of cisplatin and narciclasine were elucidated through transcriptomic analysis and subsequent validation of candidate molecules by regulating their expression. To clarify the underlying molecular mechanisms, the activation of unfolded protein responses and kinetics of a candidate protein were assessed.</p><p><strong>Results: </strong>Narciclasine inhibited viability of NSCLC tumor spheroids and augmented the sensitivity of cisplatin-resistant tumor spheroids to cisplatin by inducing apoptosis. After conducting bioinformatic analysis using RNA sequencing data and functional validation experiments, we identified NOXA as a key gene responsible for the enhanced apoptosis observed with the combination of cisplatin and narciclasine. This treatment dramatically increased NOXA while downregulating anti-apoptotic MCL1 levels. Silencing NOXA reversed the enhanced apoptosis and restored MCL1 levels, while MCL1 overexpression protected tumor spheroids from combination treatment-induced apoptosis. Interestingly, narciclasine alone and in combination with cisplatin induced unfolded protein response and inhibited general protein synthesis. Furthermore, the combination treatment increased NOXA expression through the IRE1α-JNK/p38 axis and the activation of p53. Cisplatin alone and in combination with narciclasine destabilized MCL1 via NOXA-mediated proteasomal degradation.</p><p><strong>Conclusions: </strong>We identified a natural product, narciclasine, that synergizes with cisplatin. The combination of cisplatin and narciclasine induced NOXA expression, downregulated MCL1, and ultimately induced apoptosis in NSCLC tumor spheroids. Our findings suggest that narciclasine is a potential natural product for combination with cisplatin for treatment of NSCLC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"59"},"PeriodicalIF":9.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics integration reveals Vha68-3 as a testicular aging-specific factor that coordinates spermatid elongation through mitochondrial metabolic homeostasis.","authors":"Jun Yu, Qiuru Huang, Yangbo Fu, Lei He, Cong Shen, Xia Chen, Zhiran Li, Jiaxin Li, Chenyu Wang, Xinda Wang, Binbin Yang, Ziwen Lin, Chen Qiao, Xiaofang Tan, Xiaoqing Yang, Hao Chen, Ying Zheng, Bo Zheng, Fei Sun","doi":"10.1186/s11658-025-00737-3","DOIUrl":"https://doi.org/10.1186/s11658-025-00737-3","url":null,"abstract":"<p><strong>Background: </strong>Testicular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear.</p><p><strong>Methods: </strong>Vha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome-metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography-tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies.</p><p><strong>Results: </strong>In this study, we identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome-metabolome integration, we identified pyruvate metabolism as a critical pathway disrupted by Vha68-3 deficiency. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency.</p><p><strong>Conclusions: </strong>Our findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation and propose potential therapeutic strategies to combat mitochondrial metabolic disorders in aging testes.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"58"},"PeriodicalIF":9.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunodynamic axis of fibroblast-driven neutrophil infiltration in acute pancreatitis: NF-κB-HIF-1α-CXCL1.","authors":"Qiang Wang, Xiao Zhang, Chenglong Han, Zhenyi Lv, Yi Zheng, Xuxu Liu, Zhiwei Du, Tianming Liu, Dongbo Xue, Tao Li, Liyi Wang","doi":"10.1186/s11658-025-00734-6","DOIUrl":"https://doi.org/10.1186/s11658-025-00734-6","url":null,"abstract":"<p><strong>Background: </strong>Acute pancreatitis (AP) is a sterile inflammation, and 10-20% of cases can progress to severe acute pancreatitis (SAP), which seriously threatens human life and health. Neutrophils and their extracellular traps (NETs) play an important role in the progression of AP. However, the immunodynamic factors between the excessive infiltration of neutrophils during the occurrence of AP have not been fully elucidated.</p><p><strong>Methods: </strong>Adult male C57BL/6 J mice were selected. An AP model was induced by cerulein, and a control group was set up. Single-cell sequencing technology was used to reveal the cell atlas of AP pancreatitis tissue. In vivo, the model mice were treated with anti-Ly6G antibody, DNase I, SC75741, PX-478, and SRT3109 respectively. In vitro, human pancreatic stellate cells were treated with hypoxia, H₂O₂, NAC, and JSH-2, and co-cultured with neutrophils in Transwell chambers. The severity of inflammation was evaluated, and the molecular mechanism by which fibroblasts exacerbate AP was revealed through techniques such as cell colony formation assay, cell migration assay, cell transfection, immunofluorescence, flow cytometry, Western blot, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (co-IP).</p><p><strong>Results: </strong>The study showed that the elimination of neutrophils and NETs could significantly improve AP. Single-cell RNA sequencing (scRNA-seq) indicated that both neutrophils and fibroblasts in pancreatic tissue exhibited heterogeneity during AP. Among them, neutrophils highly expressed CXCR2, and fibroblasts highly expressed CXCL1. Further experimental results demonstrated that the infiltration of neutrophils in the early stage of AP was related to the activation of fibroblasts. The activation of fibroblasts depended on the nuclear factor kappa B (NF-κB) signaling pathway induced by hypoxia. NF-κB enhanced the activation of pancreatic stellate cells (PSCs) and the secretion of CXCL1 by directly promoting the transcription of HIF-1α and indirectly inhibiting PHD2, resulting in the accumulation of HIF-1α protein. The NF-κB-HIF-1α signal promoted the secretion of CXCL1 by fibroblasts through glycolysis and induced the infiltration of neutrophils. Finally, blocking the NF-κB-HIF-1α-CXCL1 signaling axis in vivo reduced the infiltration of neutrophils and improved AP.</p><p><strong>Conclusions: </strong>This study, for the first time, demonstrated that activation of fibroblasts is one of the immunological driving factors for neutrophil infiltration and elucidated that glycolysis driven by the NF-κB-HIF-1α pathway is the intrinsic molecular mechanism by which fibroblasts secrete CXCL1 to chemotactically attract neutrophils. This finding provides a highly promising target for the treatment of AP.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"57"},"PeriodicalIF":9.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}