International Journal of Biological Sciences最新文献

{"title":"Osteocytes Produces RANKL Via Wnt-TGFβ Signaling Axis for Osteoclastogenesis.","authors":"Yujiao Liu, Lizhou Zhao, Molin Li, Weimin Gong, Xiaofang Wang, Yu Cheng, Ying Zhang, Pengtao Wang, Yisheng Luo, Yining Zhang, Yufei Shao, Makoto Mark Taketo, Teresita Bellido, Gaohai Shao, Xing Liu, Xiaolin Tu","doi":"10.7150/ijbs.117481","DOIUrl":"https://doi.org/10.7150/ijbs.117481","url":null,"abstract":"<p><p>Osteocytes are derived from osteoblasts in the mineralized matrix and are the main source of RANKL required for osteoclastogenesis. We initially found osteocytes as central target cells for Wnt/β-catenin signaling that increases RANKL expression and bone resorption in mice. However, how RANKL is regulated remains unclear. Here, we demonstrated its role and molecular mechanisms using primary osteocytes isolated from long bones. Osteocyte transcriptome sequencing revealed the most associated osteoclast differentiation in KEGG pathways with upregulated expression of <i>Tgfb1/2</i>. <i>In vivo</i> data highlight the specificity of osteocytic Wnt, rather than osteoblastic Wnt, in regulating TGFβ signaling. Activation/inactivation of osteocytic TGFβ signaling stringently promotes/inhibits RANKL expression and osteoclast differentiation in dose- and time-dependent manners. Wnt signaling increases RANKL expression through TGFβ signaling via the physical interaction of its transcription factor Smad4 with the RANKL promoter region. Mice with disrupted TGFβ signaling in osteocytes recapitulate defective osteoclastogenesis and reduced RANKL expression in osteocytes. Thus, osteocytes mediate bone resorption via Wnt-TGFβ signaling axis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5821-5841"},"PeriodicalIF":10.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280013","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":"NR5A2 (located on chromosome 1q32) inhibits ferroptosis and promotes drug resistance by regulating phospholipid remodeling in multiple myeloma.","authors":"Panpan Li, Jiadai Xu, Bei Xu, Xiaowen Hu, Yaqin Xiong, Yawen Wang, Peng Liu","doi":"10.7150/ijbs.113115","DOIUrl":"https://doi.org/10.7150/ijbs.113115","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a prevalent hematologic malignancy with improved survival rates over recent decades, although still uncurable. MM with chromosome 1q Gain (1q+) are clinically and biologically heterogeneous. In this study, we found that NR5A2, located on chromosome 1q and encoding an essential transcriptional regulator of lipid metabolism, has higher mRNA expression in 1q+ patients and could further stratify the prognosis of MM patients. Omics data were analyzed and related experiments were conducted. We demonstrated for the first time that NR5A2 promotes the proliferation and invasion of MM cells by regulating phospholipid metabolism and further inhibit ferroptosis by reducing the related specific substrate in MM cells. Through integrated analysis of the lipid metabolism and proteome, MBOAT1 and MBOAT2 were determined to be the downstream targets of NR5A2. Furthermore, it has been determined that the high expression of NR5A2 is closely related to the resistance of MM cells to dexamethasone (Dexa). Interestingly, we found for the first time that arachidonic acid co-culture with MM cells can promote their sensitivity to Dexa and significantly reverse the resistance to Dexa caused by high expression of NR5A2. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q+.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5789-5801"},"PeriodicalIF":10.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280002","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":"Remodeling the Tumor Immune Environment in Breast Cancer via Bortezomib-based Combination Therapy.","authors":"Shaojuan Huang, Qiang Chen","doi":"10.7150/ijbs.122366","DOIUrl":"https://doi.org/10.7150/ijbs.122366","url":null,"abstract":"<p><p>While proteasome inhibitors have revolutionized the treatment of hematologic malignancies and significantly improved patient survival, their efficacy in solid tumors remains limited. The recent work by Tang and colleagues demonstrates a novel combination strategy to overcome this limitation. Their study reveals that bortezomib, combined with either tetrathiomolybdate or AMD3100, synergistically kills breast cancer by downregulating expression of the proteasome subunit PSMB5. Crucially, the <i>in vivo</i> antitumor efficacy of these combinations is strictly dependent on an intact immune system, enabling cytotoxic CD8⁺ T cell responses. Although this study raises important mechanistic questions for future investigation, it significantly opens new avenues for expanding the therapeutic application of proteasome inhibitors in solid tumors.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5785-5788"},"PeriodicalIF":10.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280005","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":"Stem cells enhance their chondrogenic differentiation in hydrogels by mechanical tumbling.","authors":"Xuemiao Liu, Weiguo Zhang, Xing Wang","doi":"10.7150/ijbs.118859","DOIUrl":"https://doi.org/10.7150/ijbs.118859","url":null,"abstract":"","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5782-5784"},"PeriodicalIF":10.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280100","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":"Immunotherapy resistance in MASLD-related hepatocellular carcinoma: special immune microenvironment and gut microbiota.","authors":"Jie Jin, Kun Cheng, Mingrui Chen, Huifang Liang, Wanguang Zhang","doi":"10.7150/ijbs.117394","DOIUrl":"https://doi.org/10.7150/ijbs.117394","url":null,"abstract":"<p><p>Obesity represents a major global public health challenge. Consequently, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the primary driver of chronic liver disease globally and is currently the most rapidly accelerating factor contributing to hepatocellular carcinoma (HCC). However, current evidence indicates that immunotherapy, a cornerstone of HCC management, yields suboptimal results specifically in MASLD-related HCC (MASLD-HCC) cases. Various immune components constitute a special immune microenvironment in MASLD-HCC, including heterogeneous myeloid cells, lymphocytes and platelets. Furthermore, disruptions in the intestinal barrier, along with the ectopic presence of intestinal flora and metabolites, also influence the immune microenvironment in MASLD-HCC. Elucidating immune cells functions and their interplay with gut microbiota is critical to deciphering MASLD progression to carcinogenesis and immunotherapy resistance. This review synthesizes current insights into the immune microenvironment and gut microbiome in MASLD-HCC, identifies factors influencing the efficacy of immunotherapy, and summarizes potential therapeutic targets to provide detailed guidance for developing effective immunotherapy strategies for MASLD-HCC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5666-5690"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279638","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":"Sec10 negatively regulates antiviral immunity by downregulating NRF2-ATF4-RIG-I axis.","authors":"Peili Hou, Fuzhen Zhang, Xiaonan Sun, Hongchao Zhu, Yueyue Feng, Jun Wang, Xiaoyun Wang, Yuanyuan Han, Rui Li, Chuanhong Wang, Yingying Li, Hongmei Wang, Hongbin He","doi":"10.7150/ijbs.117430","DOIUrl":"https://doi.org/10.7150/ijbs.117430","url":null,"abstract":"<p><p>Sec10, as a central component of the eight-protein exocyst complex, plays a crucial role in the exocytosis. However, its role in antiviral immunity has remained elusive. Here, we discover that Sec10 negatively regulates antiviral immune response by downregulation of RIG-I at transcriptional level, thereby facilitating RNA replication in multiple cells. Mechanistically, we demonstrate that ATF4 binds to the RIG-I promoter and promotes RIG-I transcription, and NRF2 upregulates ATF4 activity and expression. Notably, Sec10 triggers the inactivation of the NRF2-ATF4 axis during RNA viral infection, which is, in turn restrains RIG-I transcription, attenuating antiviral IFN-I response. Importantly, Sec10 deficiency results in enhanced innate immunity, diminished SeV load and morbidity in mice. Taken together, we firstly unveil the function of Sec10 in viral infection, and elucidate its novel mechanisms of antiviral immunity via the NRF2-ATF4-RIG-I axis, which provides the potential therapeutic targets and offers new insights for antiviral drug development.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5744-5761"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280003","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":"Pathophysiology, development, and mortality of major non-communicable diseases in metabolic dysfunction-associated steatotic liver disease: A comprehensive review.","authors":"Minjeong Kang, Jihun Song, Eun Seok Kang, Seohui Jang, Taeho Kwak, Yihyun Kim, Meng Sha, Hwamin Lee, Seogsong Jeong","doi":"10.7150/ijbs.117211","DOIUrl":"https://doi.org/10.7150/ijbs.117211","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease, has emerged as a critical contributor to the global burden of non-communicable diseases (NCDs). Beyond its hepatic manifestations, MASLD is pathophysiologically connected to broader metabolic dysfunction, including insulin resistance, obesity, type 2 diabetes, and cardiovascular complications. This review critically examines the bidirectional associations between MASLD and major NCDs, including type 2 diabetes, cardiovascular disease, chronic respiratory disease, and cancer, focusing on shared mechanisms such as chronic inflammation, insulin resistance, oxidative stress, lipotoxicity, and epigenetic alterations. Furthermore, we explore disease-specific mortality patterns and mortality-related factors in MASLD patients across NCD domains. This review underscores the need for comprehensive and multidisciplinary strategies that address not only metabolic control but also systemic inflammation, immunometabolic dysregulation, and epigenetic alterations. Such integrative approaches are essential to mitigating the multisystem burden of MASLD and reducing mortality from its associated NCDs.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5691-5703"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279945","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":"dsHMGB1, released from IL-17A-induced pyroptotic prostate epithelial cells, drives M1 polarization by promoting Pfkp-mediated glycolysis via Jak2/Stat1 transcription in experimental autoimmune prostatitis.","authors":"Wenming Ma, Yi Zhang, Wenlong Xu, Yongtao Hu, Weikang Wu, Lei Chen, Li Zhang, Hexi Du, Jialin Meng, Jing Chen, Chaozhao Liang","doi":"10.7150/ijbs.113908","DOIUrl":"https://doi.org/10.7150/ijbs.113908","url":null,"abstract":"<p><p><b>Background:</b> Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder in males, characterized by an unknown mechanism and limited therapeutic efficacy. The involvement of high mobility group box 1 (HMGB1)-mediated macrophage polarization has been extensively explored in various immune-inflammatory conditions; however, its potential role in CP/CPPS has not yet been examined. <b>Method:</b> In experimental autoimmune prostatitis (EAP) mouse model, with various treatments including anti-IL-17A, Bz-ATP, or glycyrrhizic acid (GA, a HMGB1 inhibitor). In <i>vitro</i>, prostate epithelial cells (PECs) and immortalized bone marrow-derived macrophages (iBMDM) were treated with IL-17A, disulfide HMGB1 (dsHMGB1), or fludarabine (Flu, a Stat1 inhibitor). Histological analysis, immunofluorescence, TUNEL, ELISA, reactive oxygen species detection, glucose uptake, lactate assays, flow cytometry, western blot, proteome sequence, differential gene analysis, RT-qPCR, ChIP-qPCR, and dual-luciferase assay, etc. were used for the detection of phenotypes and exploration of mechanisms. <b>Results:</b> We confirmed that IL-17A could induce pyroptosis in PECs and release dsHMGB1 in <i>vitro</i>, the similar function presented in <i>vivo</i> as well, and can be reversed by Bz-ATP. Additionally, dsHMGB1 enhances glycolytic metabolism via the Jak2/Stat1 pathway, thereby promoting polarization of M1 macrophage. Pfkp, a rate-limiting enzyme involved in glycolysis, plays a critical role in this metabolic shift. ChIP-qPCR and luciferase assays demonstrated that Stat1 can transcriptionally regulate Pfkp. In the rescue experiments, we also demonstrated that GA and Flu could potentially be the therapeutic options for CP/CPPS. <b>Conclusions:</b> IL-17A-mediated pyroptosis in prostate epithelial cells triggers the release of dsHMGB1, which transcriptional regulates the key glycolytic enzyme Pfkp through the Jak2/Stat1 transcription to promote the M1 polarization of macrophages. Targeting dsHMGB1 or Stat1 could be potential therapeutic strategies for managing CP/CPPS by regulating M1 macrophage polarization and reducing inflammatory cytokines.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5725-5743"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279659","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":"Mettl1-mediated m⁷G modification of Fgfr2 regulates osteogenic and chondrogenic differentiation of mesenchymal stem cells.","authors":"Quanfeng Li, Yunhui Zhang, Pengfei Ji, Yibin Zhang, Jianan Jiang, Jiahao Jin, Zihao Yuan, Guangqi Tian, Mingxi Cai, Pei Feng, Yanfeng Wu, Wenjie Liu, Peng Wang","doi":"10.7150/ijbs.114889","DOIUrl":"https://doi.org/10.7150/ijbs.114889","url":null,"abstract":"<p><p>N7-methylguanosine (m⁷G) is a prevalent RNA modification and plays fundamental roles in embryonic stem cell self-renewal and differentiation. However, its specific contributions to mesenchymal stem cell differentiation during skeletal development remain poorly understood. In this study, we demonstrate that specific deletion of the m⁷G methyltransferase Mettl1 in mesenchymal lineage cells causes severe bone development defects, manifesting as dramatic limb shortening at birth. The absence of Mettl1 in mesenchymal stem cells significantly hinders osteoblast and chondrocyte differentiation. Integrative analyses of single-cell RNA-sequencing and m⁷G-MeRIP sequencing demonstrate that Mettl1 ablation disrupts m⁷G modifications of Fgfr2, resulting in reduced its mRNA stability. Fgfr2 downregulation impairs the PI3K-AKT and MAPK signaling pathways, which decreases Sp1 phosphorylation and promotes its ubiquitin-mediated degradation, ultimately leading to reduced transcription of Col1a1 and Col2a1. Pharmacological reactivation of Fgfr2 signaling rescues the defects caused by Mettl1 deletion. Our findings highlight the critical role of Mettl1-mediated m⁷G modification in regulating osteogenic and chondrogenic differentiation of mesenchymal stem cells during bone development and provide new insights into the regulatory mechanisms of RNA modifications in skeletal biology.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5704-5724"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279936","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":"NDR1 enhances USP9X-mediated AR deubiquitination and promotes enzalutamide resistance in castration-resistant prostate cancer.","authors":"Zeyuan Zheng, Jinxin Li, Yifan Du, Liyan Li, Qingqing Wu, Bin Liu, Haodong Wu, Zeyi Zhang, Zuodong Xuan, Yue Zhao, Huimin Sun, Chen Shao","doi":"10.7150/ijbs.114686","DOIUrl":"https://doi.org/10.7150/ijbs.114686","url":null,"abstract":"<p><p>Castration-resistant prostate cancer (CRPC) enzalutamide resistance is a significant issue in the current treatment of prostate cancer (PCa). Previously, nuclear Dbf2-related 1 (NDR1) was found to influence metastasis in PCa patients; however, the role of NDR1 in enzalutamide resistance in CRPC remains unclear. In this study, we found that after CRPC cells developed resistance to enzalutamide, NDR1 expression levels were elevated and that NDR1 expression could reduce the sensitivity of CRPC cells to enzalutamide. Furthermore, in androgen receptor (AR) positive PCa cell lines, the use of enzalutamide induced an increase in NDR1 expression levels. Further mechanistic exploration revealed that NDR1 positively regulates AR protein expression levels by promoting the deubiquitination of AR by USP9X, thereby increasing AR stability, which leads to cellular resistance to enzalutamide. Finally, we confirmed that pharmacological suppression of NDR1 by 17AAG significantly inhibited the growth of enzalutamide-resistant CRPC tumors in both <i>in vitro</i> and <i>in vivo</i> models. In summary, this study revealed that NDR1 enhances the deubiquitination of AR mediated by USP9X, improving its stability and activity and thereby maintaining the continuous activation of the androgen signaling pathway in CRPC, leading to resistance to enzalutamide treatment. These findings suggest that cotargeting NDR1 and AR may represent a novel therapeutic strategy for AR-positive CRPC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5628-5644"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279977","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}