{"title":"Inhibition of Mettl3 alleviates low-dose cisplatin-induced renal fibrosis and enhances the chemotherapeutic efficacy in mouse models of cancer.","authors":"Yuxin Xie, Huiling Li, Jian Pan, Yijian Li, Dongshan Zhang","doi":"10.7150/ijbs.117443","DOIUrl":"10.7150/ijbs.117443","url":null,"abstract":"<p><p>Cisplatin (CDDP), a commonly utilized anti-tumor drug, leads to acute kidney injury (AKI) and chronic kidney disease (CKD). The mechanisms and therapeutic approaches for injury in AKI have been extensively studied, but the mechanisms resulting in CKD are poorly comprehended and intervention methods are scarce. In the current study, we found that under different phases of the repeated low-dose CDDP treatment, Mettl3 expression was induced by two different mechanisms. In the presence of CDDP, the transcription factor Hif1-α was induced, resulting in an increase in Mettl3. When CDDP was removed, the previously increased Mettl3 caused an elevated lactate level, which formed a positive feedback loop by mutually reinforcing each other's expression via H3K18 lactylation. Functionally, we disclose that the knockout of Mettl3 in proximal tubules mitigates repeated low-dose CDDP-induced renal fibrosis both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, Mettl3 stabilizes Pfkfb3 mRNA through N6-methyladenosine (m6A) modification and subsequently induces lactate production to upregulate the PD-L1 expression via H3K18 lactylation, thereby promoting both tumor growth and CDDP-induced renal damage. Intriguingly, we discovered that Levosimendan suppresses the methyltransferase activity of Mettl3 to lower the m6A level but has no impact on the abundance of the Mettl3-Mettl14 complex. PLGA-encapsulated Levosimendan not only alleviates repeated low-dose CDDP-induced renal fibrosis, but also significantly enhances the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models by suppressing the Mettl3/Pfkfb3/lactate/ H3K18la/PD-L1 axis. Collectively, targeting Mettl3 might offer an effective therapeutic strategy during cisplatin-based chemotherapy-induced renal fibrosis, and PLGA-encapsulated Levosimendan is a potential intervention approach.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4293-4311"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mei Song, Lifen Zhang, Xiaofeng Dai, Shiliang Ji, Jiayin Shen, Weiling He
{"title":"Beyond polarization: macrophage senescence in immunoregulation and cancer therapy.","authors":"Mei Song, Lifen Zhang, Xiaofeng Dai, Shiliang Ji, Jiayin Shen, Weiling He","doi":"10.7150/ijbs.115921","DOIUrl":"10.7150/ijbs.115921","url":null,"abstract":"<p><p>Cancer incidence is increasing globally, presenting significant health challenges due to its severe impact on morbidity and mortality. As a disease closely linked to aging, the prevalence of cancer is expected to increase with increasing age, underscoring the need for comprehensive research into its mechanisms and treatments. Macrophages, which are central to the immune system, play a paradoxical dual role in cancer progression. While they can suppress tumor growth, tumor-associated macrophages (TAMs) frequently facilitate tumor development and metastasis, a complexity that is further intricate by the aging process. As macrophages transition into senescent cells, they undergo changes, including shifts in cytokine profiles, reduced phagocytic activity, and altered metabolism. These senescent macrophages contribute to cancer progression by creating an immunosuppressive environment, promoting angiogenesis, and supporting tumor invasion. This review explores the intricate functions of senescent macrophages in cancer, highlighting their implications for tumor biology and their potential as therapeutic targets. We discuss strategies to manipulate senescent macrophages to enhance current cancer therapies, emphasizing the importance of understanding their mechanisms to advance cancer treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4312-4333"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tryptophan metabolism as a target in gut microbiota, ageing and kidney disease.","authors":"Hua Miao, Shui-Juan Zhang, Xin Wu, Ping Li, Ying-Yong Zhao","doi":"10.7150/ijbs.115359","DOIUrl":"10.7150/ijbs.115359","url":null,"abstract":"<p><p>Aromatic amino acid tryptophan metabolism, particularly three main metabolism pathways including kynurenine, serotonin and indole-derived pathways are under the direct or indirect modulation of host-microbiota crosstalk in human physiology. Tryptophan metabolism is involved in the regulation of aging, immunity and intestinal homeostasis. Dysregulation of tryptophan metabolism ranging from bowel disease to kidney disease allow us to therapeutic targeting the tryptophan metabolism. This review summarizes recent advances in physiological and pathophysiological roles of tryptophan metabolism in health and disease such as ageing-related disease, bowel disease and renal disease. Decoding the sophisticated imbalance between tryptophan metabolism pathways will expedite a comprehensive understanding of the pathogenesis of human diseases and highlight the opportunities and challenges for medication research and development in multiple diseases. This review presents concept-driven diagnostic and therapeutic strategies for the management of patients with kidney disease by gut-kidney-aging axes.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4374-4387"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lavinia Petriaggi, Emanuele Giorgio, Stefania Bulotta, Alessandro Antonelli, Sonia Bonacci, Marialaura Frisina, Antonio Procopio, Licia Elvira Prestagiacomo, Annarita Giuliano, Marco Gaspari, Gianluca Santamaria, Giorgia Federico, Cristiana Galeano, Giuseppe Natali, Amerigo Giudice, Francesco Costanzo, Anna Martina Battaglia, Flavia Biamonte
{"title":"Acute Exposure to Cadmium Triggers NCOA4-Mediated Ferritinophagy and Ferroptosis in Never-Smokers Oral Cancer Cells.","authors":"Lavinia Petriaggi, Emanuele Giorgio, Stefania Bulotta, Alessandro Antonelli, Sonia Bonacci, Marialaura Frisina, Antonio Procopio, Licia Elvira Prestagiacomo, Annarita Giuliano, Marco Gaspari, Gianluca Santamaria, Giorgia Federico, Cristiana Galeano, Giuseppe Natali, Amerigo Giudice, Francesco Costanzo, Anna Martina Battaglia, Flavia Biamonte","doi":"10.7150/ijbs.111228","DOIUrl":"10.7150/ijbs.111228","url":null,"abstract":"<p><p>Cadmium (Cd), a carcinogenic component of tobacco, is a recognized risk factor for oral squamous cell carcinoma (OSCC). However, the molecular mechanisms underlying Cd-induced cytotoxicity in OSCC remain largely undefined. Here, we demonstrate that acute Cd exposure triggers ferroptosis in CAL27 OSCC cells derived from never-smokers, but not in SCC154 cells derived from smokers. Mechanistically, Cd outcompetes Fe, causing early iron depletion and activating the nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. This process enhances the labile iron pool, promotes mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, and ferroptotic cell death. Notably, iron supplementation rescues CAL27 cells from Cd-induced damage, while exacerbating iron deficiency through transferrin receptor CD71 silencing amplifies cytotoxicity. Conversely, OSCC cells from smokers exhibit resistance to Cd toxicity, likely due to the overexpression of metallothionein 2A (MT2A), a heavy metal detoxification protein. Collectively, this study provides the evidence that ferritinophagy may act as a critical upstream driver of Cd-induced ferroptosis in OSCC cells derived from never-smokers, paving the way for potential ferroptosis-targeted therapeutic strategies in Cd-associated malignancies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4131-4152"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enhancing CAR-T Cell Metabolic Fitness and Memory Phenotype for Improved Efficacy against Hepatocellular Carcinoma.","authors":"Jinqi You, Xinyi Yang, Jingjing Zhao, Hao Chen, Yan Tang, Dijun Ouyang, Yuanyuan Liu, Yan Wang, Songzuo Xie, Yuanyuan Chen, Jinghao Liao, Tong Xiang, Jianchuan Xia, Chaopin Yang, Desheng Weng","doi":"10.7150/ijbs.110406","DOIUrl":"10.7150/ijbs.110406","url":null,"abstract":"<p><p>The persistence of chimeric antigen receptor (CAR) T cells in the tumor microenvironment limits their antitumor effects against solid tumors. Many studies have reported that the <i>in vitro</i> phenotype and metabolism of CAR-T cells correlates with their <i>in vivo</i> antitumor activity. Herein, we constructed PD-1 scFv-secreting and CD133-specific CAR-T (referred to as CAR-T) cells based on our previous work. We found that suitable concentration metformin-treated CAR-T (mCAR-T) cells exhibited an increased memory phenotype and demonstrated stronger and faster antitumor abilities with a reduced exhaustion phenotype. Using RNA sequencing, transmission electron microscope, and metabolic analysis, we discovered enhanced mitochondrial biogenesis and metabolism in CAR-T cells treated with 10 μM metformin, is associated with increased peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) expression, promotion of signal transducer and activator of transcription (STAT)3 and inhibition of STAT5 phosphorylation. This resulted in enhanced antitumor effects of mCAR-T cells in both subcutaneous and orthotopic xenograft models. Importantly, in some relapsed hepatocellular carcinoma (HCC) patients, high CD133 expression was observed in their paired primary or metastatic tumor sections. Our study revealed that enhancing metabolic fitness and central memory by <i>in vitro</i> metformin treatment is an effective strategy to improve the efficacy of CAR-T cell therapy, potentially benefiting some relapsed HCC patients.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4231-4251"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liwen Feng, Guangqin Xiao, Yuting Chen, Ting Ye, Li Fan, Yuxiu Xie, Ting Mei, Lei Wang, Jingjing Ge, Chengzhi Ye, Jing Chen
{"title":"Cancer-associated Fibroblast-like Cells Promote Osteosarcoma Metastasis by Upregulation of Phosphoserine Aminotransferase 1 and Activation of the mTOR/S6K Pathway.","authors":"Liwen Feng, Guangqin Xiao, Yuting Chen, Ting Ye, Li Fan, Yuxiu Xie, Ting Mei, Lei Wang, Jingjing Ge, Chengzhi Ye, Jing Chen","doi":"10.7150/ijbs.109169","DOIUrl":"10.7150/ijbs.109169","url":null,"abstract":"<p><p>Metastasis remains a major obstacle limiting the survival of patients with osteosarcoma (OS). Cross-talk between cancer-associated fibroblasts (CAFs) and OS cells has been found to facilitate metastasis, although the effects of CAFs on OS cell metabolism are poorly understood. Here, conditioned medium from OS cells was used to activate CAF-like cells, which was found to promote OS migration and the epithelial-mesenchymal transition. Metabolomics analysis showed that treatment of OS cells with CAFs-conditioned medium significantly altered the levels of phosphoserine aminotransferase 1 (PSAT1), a key serine synthase. CAF-induced OS cell migration was inhibited by PSAT1 knockdown by siRNA, and PSAT1 was found to promote migration through the PI3K/mTOR/S6K pathway. The influence of CAFs on OS metastasis was blocked by PSAT1 knockdown and mTOR inhibitors <i>in vitro</i> and <i>in vivo</i>. In conclusion, the findings suggest that PSAT1 and the mTOR/S6K pathway have the potential as targets for preventing OS metastasis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4153-4171"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway.","authors":"Zongji Zheng, Jiaqi Chen, Xiaoquan Xue, Xiaoqin Ma, Shuting Zhang, Ming Wang, Yaoming Xue, Yijie Jia","doi":"10.7150/ijbs.109799","DOIUrl":"10.7150/ijbs.109799","url":null,"abstract":"<p><p>During diabetic kidney disease (DKD), tubulointerstitial fibrosis persists, although several methods have been applied to reduce albuminuria levels. In this research, we found that bovine serum albumin (BSA)-induced renal tubular cell injury could also spread to normal tubular cells through exosomes, which may explain why tubulointerstitial fibrosis persists. Our previous studies revealed that SESN2 overexpression alleviates tubular dysfunction. In this study, we showed that SESN2 overexpression in donor HK2 cells interrupted this \"doom loop\" and confirmed that SESN2 may mediate this process by reducing exosome secretion. By using RNA-seq and IP-MS, we found that SESN2 could inhibit BSA-induced Rab-7a ubiquitination, thus promoting autophagosome and lysosome fusion and accelerating MVB degradation. We also showed that SESN2 promotes the nuclear translocation of TFEB through the mTOR pathway, thus further alleviating lysosomal function and promoting MVB degradation. We also found that SESN2 not only slowed DKD progression but also promoted renal tubular cell secretion of protective exosomes, which also slowed DKD progression. In conclusion, SESN2 can interrupt the progression of albuminuria-induced tubular injury by inhibiting exosome secretion and promoting MVB degradation. Thus, SESN2 may be a new therapeutic target for DKD treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4215-4230"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers.","authors":"Yilin Li, Jiaqi You, Zifang Zou, Guanghao Sun, Yuqing Shi, Yanbin Sun, Shun Xu, Xin Zhang","doi":"10.7150/ijbs.114222","DOIUrl":"10.7150/ijbs.114222","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is dynamically shaped by interactions between tumor cells, immune cells, and stromal components. Among these, tumor-associated macrophages (TAMs) play dual roles in tumor progression. Exosomes are key mediators of intercellular communication and are crucial for modulating macrophage polarization. This review systematically summarizes the role of HIF-1α as the central regulator of tumor-derived exosomes under hypoxic conditions. Under endoplasmic reticulum stress (ERS), the STAT3 and PI3K/AKT/mTOR pathways activation is mediated by the inactivation of the Hsp90/Hippo pathway, which induces the expression of LncRNA HMMR-AS1 and specific miRNAs (<i>e.g.,</i> miR-1246, let-7a, miR-301a-3p, <i>etc</i>.). Furthermore, the IRE1/PERK pathway regulates exosome secretion by carrying miR-23a-3p and miR-27a-3p or directly delivering PD-L1 protein, thus activating the PI3K/AKT pathway, inhibiting PTEN, and upregulating PD-L1 expression as well as increasing the M2 polarization of macrophages. This study also summarized the important matrices of exosomes' involvement in the interaction between tumor cells and macrophages in different systemic malignant tumors. Moreover, the bidirectional crosstalk between TAM-derived exosomes and other TME components (<i>e.g.,</i> CD8+ T cells, fibroblasts) was also evaluated, which indicated their roles in immune evasion and metastasis. Further, engineering strategies, such as receptor-targeted exosomes and short palindromic repeats interference (CRISPRi)-based transcriptional silencing, were also discussed as emerging tools to enhance exosome specificity and therapeutic efficacy. This study proposes a roadmap for translating engineered exosomes into clinical immunotherapy regimens by integrating recent advances in spatial omics and artificial intelligence, and also addresses challenges in exosome isolation, stability, and biosafety.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4187-4214"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.","authors":"Zhiwei Xu, Xiangzheng Gao, Dade Rong, Jingyao Wang, Liangliang Gao, Mingzhu Tang, Yiguan Chen, Yichi Zhang, Liming Xie, Liming Wang, Guang Lu, Jia-Hong Lu, Wei Liu, Han-Ming Shen","doi":"10.7150/ijbs.112672","DOIUrl":"10.7150/ijbs.112672","url":null,"abstract":"<p><p>Mitophagy is a selective form of autophagy for the clearance of damaged and dysfunctional mitochondria via the autophagy-lysosome pathway. As mitochondria are the most important metabolic organelles, the process of mitophagy is tightly regulated by glucose metabolism. At present, it is known that glucose is required for the mitophagy process, while the underlying mechanisms remain to be further elucidated. In this study, we establish a novel regulatory role of glucose metabolism in mitophagy via protein O-GlcNAcylation. First, we found that acute mitochondrial damage enhanced glucose uptake and promoted protein O-GlcNAcylation. Second, we provided evidence that protein O-GlcNAcylation promotes PINK1-Parkin-dependent mitophagy. Next, we attempted to illustrate the molecular mechanisms underlying the regulation of O-GlcNAcylation in mitophagy by focusing on PTEN-induced kinase 1 (PINK1). One important observation is that PINK1 is O-GlcNAcylated upon acute mitochondrial damage, and suppression of O-GlcNAcylation impairs PINK1 protein stability and its phosphorylated ubiquitin, leading to impaired mitophagy. More importantly, we found that glucose metabolism promotes mitophagy via regulating O-GlcNAcylation. Taken together, this study demonstrates a novel regulatory mechanism connecting glucose metabolism with mitophagy via O-GlcNAcylation of PINK1. Therefore, targeting the O-GlcNAcylation may provide new strategies for the modulation of mitophagy and mitophagy-related human diseases.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4252-4269"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenfang Zheng, Qifeng Luo, Xuehui Wang, Xiqian Zhou, Danrong Ye, Kaiyao Hua, Lin Fang
{"title":"NASP Promotes Triple-negative Breast Cancer Progression and Metastasis by Stabilizing YAP in a USP15-Dependent Way.","authors":"Wenfang Zheng, Qifeng Luo, Xuehui Wang, Xiqian Zhou, Danrong Ye, Kaiyao Hua, Lin Fang","doi":"10.7150/ijbs.99438","DOIUrl":"10.7150/ijbs.99438","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) was a subtype of breast cancer with high rate of metastasis and poor prognosis. Thus, it is urgent to explore the underlying mechanism of TNBC metastasis and seek for potential therapeutic targets to improve the prognosis of TNBC patients. Here we reported that nuclear autoantigenic sperm protein (NASP) was highly expressed in TNBC and related to poor prognosis of TNBC patients. NASP acted as an oncogene that promoted the progression and metastasis of TNBC. Mechanistically, high expression of NASP in TNBC was induced by SRSF1-mediated stabilization of NASP mRNA. NASP interacted with USP15 and facilitated its activity, which resulted in the deubiquitylation and stabilization of YAP by erasing K48-linked polyubiquitination. Moreover, in vivo studies validated the role of NASP in stimulating TNBC growth and metastasis. Altogether, NASP promoted TNBC progression and metastasis by stabilizing YAP in a USP15-dependent way. It might provide new insights and potential therapeutic targets for preventing TNBC metastasis and improving the prognosis of TNBC patients.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4172-4186"},"PeriodicalIF":8.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}