International Journal of Biological Sciences最新文献

{"title":"TAGLN-RhoA/ROCK2-SLC2A3-mediated Mechano-metabolic Axis Promotes Skin Fibrosis.","authors":"Xinwei Cheng, Zhen Gao, Jin Zhang, Hongkun Zheng, Shengzhou Shan, Jia Zhou","doi":"10.7150/ijbs.104484","DOIUrl":"https://doi.org/10.7150/ijbs.104484","url":null,"abstract":"<p><p>Skin fibrotic diseases are characterized by abnormal fibroblast function and excessive deposition of extracellular matrix. Our previous single-cell sequencing results identified an enriched fibroblast subcluster in skin fibrotic tissues that highly expresses the actin cross-linking cytoskeletal protein Transgelin (TAGLN), which bridges the mechanical environment of tissues and cellular metabolism. Therefore, we aimed to investigate the role of TAGLN in the pathogenesis of skin fibrosis. Transwell, wound healing, collagen gel contraction assay, immunofluorescence and RNA-seq analyses were used to validate and explore the potential mechanisms of the TAGLN-RhoA/ROCK2-SLC2A3-mediated mechano-metabolic axis in dermal fibrosis. The therapeutic efficacy of targeting TAGLN was validated using a bleomycin-induced mouse model of skin fibrosis. Functional assays revealed that downregulation of TAGLN inhibited motility and secretory function of fibroblasts, including invasion, migration, contraction, and collagen secretion. The glucose carrier SLC2A3 was identified as one of the downstream targets of TAGLN by RNA-sequencing analysis and further validation. We further demonstrated that TAGLN regulates the expression of SLC2A3 through the RhoA/ROCK2 pathway, a key pathway of mechanotransduction, thereby affecting glycolysis and motility of fibroblasts. This study reveals the existence of the TAGLN-RhoA/ROCK2-SLC2A3 mechano-metabolic axis in skin fibrotic diseases and provides a promising target for its clinical treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"658-670"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948292","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":"Toll-like receptor adaptor protein TIRAP has specialized roles in signaling, metabolic control and leukocyte migration upon wounding in zebrafish larvae.","authors":"Li Liu, Wanbin Hu, Fatima Didar Kerman, Herman P Spaink","doi":"10.7150/ijbs.101055","DOIUrl":"https://doi.org/10.7150/ijbs.101055","url":null,"abstract":"<p><p>The TIRAP protein is an adaptor protein in TLR signaling which links TLR2 and TLR4 to the adaptor protein Myd88. The transcriptomic profiles of zebrafish larvae from a <i>tirap</i>, <i>myd88</i> and <i>tlr2</i> mutant and the corresponding wild type controls under unchallenged developmental conditions revealed a specific involvement of <i>tirap</i> in calcium homeostasis and myosin regulation. Metabolomic profiling showed that the <i>tirap</i> mutation results in lower glucose levels, whereas a <i>tlr2</i> mutation leads to higher glucose levels. A tail-wounding zebrafish larval model was used to identify the role of <i>tirap</i> in leukocyte migration to tissue wounding. We found that more neutrophils were recruited to the wounded region in the <i>tirap</i> mutant larvae compared to the wild type controls, whereas there was no difference in macrophage recruitment. In contrast, published data show that <i>tlr2</i> and <i>myd88</i> mutants recruit fewer neutrophils and macrophages to the wounds. Based on cell tracking analysis, we demonstrate that the neutrophil migration speed is increased in the <i>tirap</i> mutant in contrast to neutrophil behavior in <i>myd88</i> and <i>tlr2</i> mutants. In conclusion, we show that <i>tirap</i> plays specialized roles distinct from <i>tlr2</i> and <i>myd88</i> in signaling, metabolic control, and in regulating neutrophil migration speed upon wounding.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"823-841"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948371","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":"S6K1 is a Targetable Vulnerability in Tumors Exhibiting Plasticity and Therapy Resistance.","authors":"Saptadwipa Ganguly, Ravshan Burikhanov, Vitaliy M Sviripa, Sally Ellingson, Jieyun Jiang, Christian M Gosser, David Orren, Eva M Goellner, Gautham G Shenoy, Mahadev Rao, John D'Orazio, Christine F Brainson, Chang-Guo Zhan, Peter H Spielmann, David S Watt, Vivek M Rangnekar","doi":"10.7150/ijbs.96672","DOIUrl":"10.7150/ijbs.96672","url":null,"abstract":"<p><p><b>Background:</b> Most tumors initially respond to treatment, yet refractory clones subsequently develop owing to resistance mechanisms associated with cancer cell plasticity and heterogeneity. <b>Methods:</b> We used a chemical biology approach to identify protein targets in cancer cells exhibiting diverse driver mutations and representing models of tumor lineage plasticity and therapy resistance. An unbiased screen of a drug library was performed against cancer cells followed by synthesis of chemical analogs of the most effective drug. The cancer subtype target range of the leading drug was determined by PRISM analysis of over 900 cancer cell lines at the Broad Institute, MA. RNA-sequencing and enrichment analysis of differentially expressed genes, as well as computational molecular modeling and pull-down with biotinylated small molecules were used to identify and validate RPS6KB1 (p70S6K or S6K1) as an essential target. Genetic restoration was used to test the functional role of S6K1 in cell culture and xenograft models. <b>Results:</b> We identified a novel derivative of the antihistamine drug ebastine, designated Super-ebastine (Super-EBS), that inhibited the viability of cancer cells representing diverse KRAS and EGFR driver mutations and models of plasticity and treatment resistance. Interestingly, PRISM analysis indicated that over 95% of the diverse cancer cell lines tested were sensitive to Super-EBS and the predicted target was the serine/threonine kinase S6K1. S6K1 is upregulated in various cancers relative to counterpart normal/benign tissues and phosphorylated-S6K1 predicts poor prognosis for cancer patients. We noted that inhibition of S6K1 phosphorylation was necessary for tumor cell growth inhibition, and restoration of phospho-S6K1 rendered tumor cells resistant to Super-EBS. Inhibition of S6K1 phosphorylation by Super-EBS induced caspase-2 dependent apoptosis <i>via</i> inhibition of the Cdc42/Rac-1/p-PAK1 pathway that led to actin depolymerization and caspase-2 activation. The essential role of S6K1 in the action of Super-EBS was recapitulated in xenografts, and knockout of S6K1 abrogated tumor growth in mice. <b>Conclusion:</b> S6K1 is a therapeutic vulnerability in tumors exhibiting intrinsic and/or acquired resistance to treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"454-472"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948287","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":"Regulation of INPP5E in Ciliogenesis, Development, and Disease.","authors":"Abdulaziz Hakeem, Shuying Yang","doi":"10.7150/ijbs.99010","DOIUrl":"10.7150/ijbs.99010","url":null,"abstract":"<p><p>Inositol polyphosphate-5-phosphatase E (INPP5E) is a 5-phosphatase critically involved in diverse physiological processes, including embryonic development, neurological function, immune regulation, hemopoietic cell dynamics, and macrophage proliferation, differentiation, and phagocytosis. Mutations in <i>INPP5E</i> cause Joubert and Meckel-Gruber syndromes in humans; these are characterized by brain malformations, microphthalmia, situs inversus, skeletal abnormalities, and polydactyly. Recent studies have demonstrated the key role of INPP5E in governing intracellular processes like endocytosis, exocytosis, vesicular trafficking, and membrane dynamics. Moreover, it regulates cellular signaling pathways by dephosphorylating the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate, phosphatidylinositol 4,5-bisphosphate, and phosphatidylinositol 3,5-bisphosphate. Despite recent advances, knowledge gaps persist regarding the function and molecular mechanism of INPP5E in various cells and species. This review integrates recent findings on the role of INPP5E in regulating cellular function, development, and the pathogenesis of various human disorders, emphasizing the molecular mechanism by which INPP5E regulates primary cilia assembly and function and critical signaling pathways. Identifying the importance of INPP5E in healthy and diseased states can advance our understanding of cellular processes and disease pathogenesis and provide a foundation for developing targeted therapeutic interventions.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"579-594"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055937","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":"Tail Fin Regeneration in Zebrafish: The Role of Non-canonical Crosstalk Between STAT3 and Vitamin D Pathway.","authors":"Annachiara Tesoriere, Rachele Ghirardo, Francesca Terrin, Francesco Sernesi, Giacomo Meneghetti, Luisa Dalla Valle, Alberto Dinarello, Francesco Argenton","doi":"10.7150/ijbs.96400","DOIUrl":"10.7150/ijbs.96400","url":null,"abstract":"<p><p>Stat3 is a transcription factor with a key role in cell proliferation and migration. Using the <i>stat3^-/-</i> zebrafish line we showed that the <i>stat3</i> genetic ablation results in a marked decrease of tail fin regrowth, demonstrating that this transcription factor is fundamental in the regeneration process. Stat3 activity is finely modulated by post-translational modifications that occur in several residues of the protein (i.e., Y705 and S727 phosphorylation), with tissue-specific effects. Using the newly generated <i>stat3^S→A751</i> zebrafish line, we demonstrated that the Stat3 phosphorylation in the non-canonical S751 site (homologous of mammalian serine 727) is required for the regeneration of tail fin in both larval and adult stage, even if this phosphorylation has largely been reported to have marginal roles in Stat3 activity. Our analysis showed that both <i>stat3^-/-</i> and <i>stat3^S→A751</i> mutant zebrafish lines have alterations in the expression of genes involved in epithelial and bone tissue regeneration, including genes coding for the vitamin D signaling pathway. Interestingly, the reduced regeneration activity in zebrafish <i>stat3^-/-</i> and <i>stat3^A751/A751</i> larvae is partially rescued by vitamin D treatment. Together, these results reveal a Stat3-vitamin D co-regulatory mechanism during zebrafish tail fin regeneration.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 1","pages":"271-284"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914698","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":"Glycine Decarboxylase Regulates Renal Carcinoma Progression via Interferon Stimulated Gene Factor 3-Mediated Pathway.","authors":"Thi Tuyet Mai Pham, Mikyung Kim, Thuy Quynh Nhu Nguyen, Jae-Hyung Park, Jee In Kim, Ji Hae Seo, Jin Young Kim, Eunyoung Ha","doi":"10.7150/ijbs.104458","DOIUrl":"https://doi.org/10.7150/ijbs.104458","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is considered as a \"metabolic disease\" due to various perturbations in metabolic pathways that could drive cancer development. Glycine decarboxylase (GLDC) is a mitochondrial enzyme that takes part in the oxidation of glycine to support nucleotide biosynthesis via transfer of one-carbon units. Herein, we aimed to investigate the potential role of GLDC in RCC development. We found that GLDC depletion diminished nucleotide synthesis and promoted reactive oxygen species (ROS) generation to repress RCC progression, which was reversed by repletion of deoxynucleosides. Additionally, <i>in vitro</i> and <i>in vivo</i> studies revealed that GLDC plays an important role in regulation of proliferation and tumor growth via interferon stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of interferon regulatory factor 9 (IRF9) and signal transducer and activator of transcription 2 (STAT2) were elevated in GLDC knock-downed cells and decreased in GLDC over-expressed cells. Double knock-down of STAT2 and IRF9 in GLDC-deficient cells rescued GLDC depletion-induced decrease in cell proliferation. Furthermore, GLDC depletion increased cisplatin-and doxorubicin-induced DNA damage through ISGF3 pathway, leading to cell cycle dysregulation and increased mitotic catastrophe. These findings reveal that GLDC regulates RCC progression via ISFG3-mediated pathway and offers a promising strategy for RCC treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"772-788"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948093","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":"The Cyclin-Dependent Kinase 8 Inhibitor E966-0530-45418 Attenuates Pulmonary Fibrosis <i>In Vitro</i> and <i>In Vivo</i>.","authors":"Ching-Hsuan Chou, Wei-Jan Huang, Kai-Cheng Hsu, Jui-Yi Hsu, Tony Eight Lin, Chia-Ron Yang","doi":"10.7150/ijbs.105826","DOIUrl":"https://doi.org/10.7150/ijbs.105826","url":null,"abstract":"<p><p>Pulmonary fibrosis (PF) is a high-mortality lung disease with limited treatment options, highlighting the need for new therapies. Cyclin-dependent kinase 8 (CDK8) is a promising target due to its role in regulating transcription via the TGF-β/Smad pathway, though CDK8 inhibitors have not been thoroughly studied for PF. This study aims to evaluate the potential of E966-0530-45418, a novel CDK8 inhibitor, in mitigating PF progression and explores its underlying mechanisms. We discovered that CDK8 is upregulated in lung tissues from idiopathic pulmonary fibrosis patients and in a bleomycin-induced PF mouse model. Our study further revealed that E966-0530-45418 inhibits PF progression by attenuating the activity of the transcription factor Smad3, which is involved in TGF-β1/Smad signaling, along with RNA polymerase II to downregulate fibrosis-associated protein expression in alveolar epithelia and lung fibroblasts and consequently mitigate myofibroblast differentiation and collagen deposition. E966-0530-45418 also blocks STAT3 signaling to obstruct M2 macrophage polarization, further suppressing PF progression. Moreover, E966-0530-45418 administration ameliorated lung function deterioration and lung parenchymal destruction in the bleomycin-induced PF mouse model. These findings indicate that E966-0530-45418 holds promise as a pioneering CDK8 inhibitor for treating PF.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"685-707"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948311","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":"TEAD1 Prevents Necroptosis and Inflammation in Cisplatin-Induced Acute Kidney Injury Through Maintaining Mitochondrial Function.","authors":"Melanie Tran, Baihai Jiao, Hao Du, Dong Zhou, Vijay Yechoor, Yanlin Wang","doi":"10.7150/ijbs.104335","DOIUrl":"10.7150/ijbs.104335","url":null,"abstract":"<p><p>Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1^CON) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1^PKO) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1^PKO mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1^CON mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 2","pages":"565-578"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948294","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":"Artemisinin Suppressed Melanoma Recurrence and Metastasis after Radical Surgery through the KIT/PI3K/AKT Pathway.","authors":"Zhiwei Zhou, Mohd Farhan, Xingan Xing, Wenshu Zhou, Ruohong Lin, Shan Zeng, Mengfang Li, Wenhua Zheng","doi":"10.7150/ijbs.97341","DOIUrl":"10.7150/ijbs.97341","url":null,"abstract":"<p><p>Cancer radical surgery is the primary treatment for melanoma, but almost all malignant melanoma patients get recurrence and metastasis after surgery and are eventually dead. This clinical dilemma appeals to better drugs for post-surgery therapy. Artemisinin is a safe and effective antimalarial drug used in the clinic for decades. However, no information is available regarding the effect of Artemisinins on melanoma recurrence and metastasis after tumor excision. In the present study, we established a post-surgery tumor model on balb/c nude mice, and we found that subclinical dosages of Artemisinin significantly blocked recurrence, metastasis, and extended survival time of mice after tumor excision. Similar results were obtained in the <i>in vitro</i> experiments with B16 and A375 cell lines. Further experiments confirmed that Artemisinin inhibits melanoma <i>in vitro</i> and <i>in vivo</i> after radical surgery by the c-KIT/PI3K/AKT signaling pathway. Our findings support the therapeutic potential of Artemisinin in malignant melanoma after surgery.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 1","pages":"75-94"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914554","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":"IGF1R Enhances Calcium Oxalate Monohydrate-Induced Epithelial-Mesenchymal Transition by Reprogramming Metabolism via the JAK2/STAT3 Signaling.","authors":"Jiashan Pan, Yi Zhang, Rui Yao, Mo Yang, Xike Mao, Zhenyu Song, Yuexian Xu, Yang Chen, Bingbing Hou, Xiaoying Liu, Wei Wang, Zongyao Hao","doi":"10.7150/ijbs.104311","DOIUrl":"10.7150/ijbs.104311","url":null,"abstract":"<p><p><b>Background:</b> Kidney stone disease is a major risk factor for impaired renal function, leading to renal fibrosis and end-stage renal disease. High global prevalence and recurrence rate pose a significant threat to human health and healthcare resources. Investigating the mechanisms of kidney stone-induced injury is crucial. <b>Materials and Methods:</b> We examined the relationship between insulin-like growth factor 1 receptor (IGF1R) and epithelial-mesenchymal transition (EMT) at three levels: in patients with kidney stones, in mice induced with glyoxalate crystals, and in HK2 cells stimulated with calcium oxalate monohydrate (COM). RNA sequencing (RNA-seq) and untargeted metabolomics were used to investigate IGF1R's biological mechanisms, followed by <i>in vivo v</i>alidation in mice. <b>Results:</b> IGF1R was elevated in the kidney stone model, which was significantly associated with EMT progression. RNA-seq analysis indicated that IGF1R enhances EMT through the JAK2/STAT3 pathway. Further experiments at mRNA and protein levels confirmed the activation of this pathway regulated by IGF1R, promoting EMT. Additionally, untargeted metabolomics revealed that IGF1R drives the activation of lactate dehydrogenase A (LDHA) in glycolysis, further facilitating EMT. <i>In vivo</i> experiments confirmed that IGF1R increases LDHA activity through the activation of the JAK2/STAT3 pathway, thereby enhancing the EMT. <b>Conclusion:</b> IGF1R promotes EMT in COM-induced kidney injury by activating LDHA via the JAK2/STAT3 signaling.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 1","pages":"415-432"},"PeriodicalIF":8.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914664","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}