Yanxu Chen , Qiang Zhang , Wenyu Xie , Pengfei Gao , Zhaowei Hu , Shenghui Wu , Zirong Bi , Huanxi Zhang , Yifang Gao , Changxi Wang , Longshan Liu
{"title":"NOTCH signaling orchestrates the inflammatory-fibrotic continuum of macrophages in renal allograft rejection","authors":"Yanxu Chen , Qiang Zhang , Wenyu Xie , Pengfei Gao , Zhaowei Hu , Shenghui Wu , Zirong Bi , Huanxi Zhang , Yifang Gao , Changxi Wang , Longshan Liu","doi":"10.1016/j.yexcr.2025.114711","DOIUrl":"10.1016/j.yexcr.2025.114711","url":null,"abstract":"<div><h3>Background</h3><div>Chronic rejection is a major cause of long-term kidney allograft failure, characterized by persistent inflammation and progressive fibrosis. Macrophages are central mediators of this process, but their phenotypic heterogeneity and regulatory mechanisms in chronic rejection remain incompletely understood.</div></div><div><h3>Methods</h3><div>We performed single-cell transcriptomic analysis on renal allograft biopsies from patients with different types of rejection and on a time-course rat model of chronic rejection. Macrophage subsets were identified through transcriptional profiling and Pseudotime trajectory analysis. Ligand–receptor analysis defined upstream intercellular communication, while in vitro assays using THP-1 macrophages evaluated responses to Jagged1 stimulation under polarizing conditions.</div></div><div><h3>Results</h3><div>A distinct TGFB<sup>+</sup>CD86<sup>+</sup> macrophage subset exhibiting both pro-inflammatory and pro-fibrotic features was identified. This population, enriched in mixed rejection, occupied an intermediate position along the inferred macrophage trajectory and displayed dual ontogeny. It received Jagged1–NOTCH2 signals from mesenchymal-transitioned tubular epithelial cells and inflammatory inputs from infiltrating T cells. In vitro, co-stimulation with soluble Jagged1 under M1-polarizing conditions induced a similar hybrid phenotype. In the rat model, a phenotypically comparable subset, provisionally termed M2b, appeared early post-transplantation and was later replaced by M2a macrophages as fibrosis progressed. Ligand–receptor analysis confirmed conserved Jagged1–NOTCH2 signaling regulatory axis in vivo.</div></div><div><h3>Conclusion</h3><div>In summary, we identify a transitional TGFB<sup>+</sup>CD86<sup>+</sup> macrophage population governed by JAG1–NOTCH2 signaling, bridging immune activation and fibrotic remodeling. Modulating this pathway may offer a therapeutic approach to reshape macrophage differentiation and mitigate chronic rejection.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 2","pages":"Article 114711"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"tsRNA-10105-enriched Migrasomes Mediate Hepatocellular Carcinoma Immunosuppressive Microenvironment by Inducing M2 Macrophage Polarization.","authors":"Ruiyao Zhou, Limin Pan, Yu Zeng, Yu Zhou, Haifeng Zhang, Shengguo Zhang, Xiao Hu","doi":"10.1016/j.yexcr.2025.114729","DOIUrl":"https://doi.org/10.1016/j.yexcr.2025.114729","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is characterized by a complex immunosuppressive microenvironment, which significantly influence tumor progression. Migrasomes, newly identified extracellular vesicles, have emerged as a novel mode of intercellular communication. However, their roles in HCC immune microenvironment are rarely studied. Here, we observed the migrasome markers and M2 polarization levels in HCC patient tissues using immunofluorescence. Migrasomes were isolated from HCC cells and characterized using electron microscopy, immunofluorescence, and Western blot. The effects of migrasomes on macrophage polarization and HCC progression were investigated in vitro and in vivo. Small RNA-seq was conducted to screen for key tsRNA. We discovered that the levels of the migrasome marker and M2 macrophage marker were elevated in liver tumor tissues. Migrasomes derived from HepG2 induced macrophage M2 polarization, as indicated by the increased expression of M2 polarization marker, and the suppressed expression of M1 polarization marker. Macrophages treated with these migrasomes further stimulated the proliferation, migration, and invasion of malignant cells in vitro and augmented tumor growth and metastasis in vivo. Compared to the healthy individuals, the sera of HCC patients demonstrated elevated expression of tsRNA-10105 in migrasomes. Inhibition of tsRNA-10105 significantly abolished the inducing effect of cancer cell migrasomes on the M2 macrophages polarization. Our findings indicate that migrasome-derived tsRNA-10105 from HCC cells can induce the M2 macrophages polarization, which in turn augments survival and migration of HCC cells. This work provides insights into the mechanisms of the immunosuppressive microenvironment in HCC and offers novel perspectives for the immunotherapy of liver cancer.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"114729"},"PeriodicalIF":3.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luca Pontiggia , Vanuchija Someswaran , Roth Devi Long , Mahrukh Riaz , Jonas Lussi , Bradley J. Nelson , Agnes S. Klar , Thomas Biedermann , Ueli Moehrlen
{"title":"Simple method for the production of rete ridges in human dermo-epidermal skin substitutes","authors":"Luca Pontiggia , Vanuchija Someswaran , Roth Devi Long , Mahrukh Riaz , Jonas Lussi , Bradley J. Nelson , Agnes S. Klar , Thomas Biedermann , Ueli Moehrlen","doi":"10.1016/j.yexcr.2025.114694","DOIUrl":"10.1016/j.yexcr.2025.114694","url":null,"abstract":"<div><div>The engineering of autologous dermo-epidermal skin substitutes aims to replicate the functional and structural properties of normal human skin for treating severe burns, trauma, congenital giant nevi, and necrosis-inducing diseases. We established autologous dermo-epidermal skin analogues, the quality of which is presently being assessed in phase II and III trials.</div><div>A primary challenge we are facing involves the incorporation of undulating epidermal extensions, known as rete ridges, into the dermis. This integration enhances mechanical stiffness at the dermal-epidermal junction and extend the capillary-epidermal interface, thereby facilitating wound healing.</div><div>To address this challenge, we employed a refined version of our laboratory's established protocol, utilizing simpler technologies. We specifically used a hydrogel formulated from pure type I collagen mixed with fibroblasts, which was then subjected to plastic compression to ensure mechanical stability. To introduce dermal papillae, we modified the surface of the compression piston to create a 'wavy' texture, mimicking natural skin. This piston acts as a mould during both the gelation and plastic compression phases of the hydrogel. As a result, we successfully developed rete ridges with the expected dimensions, but their stability after keratinocyte seeding remains an issue.</div><div>In summary, while operational simplicity and avoidance of potentially toxic crosslinkers, provides a safe and easily adoptable route to replicating the natural structure of the rete ridges, we still face challenges in controlling ridge dimensions and maintaining the integrity of the dermal-epidermal junction structure.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114694"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Quan Wang , Jinsheng Huang , Shichao Wu , Jintian Wang , Tingting Yu , Wei Wei , Tao Yang , Xuelei Wu , Jianning Zhai , Xiaopeng Zhang
{"title":"Neuro-immuno-stromal context in colorectal cancer: An enteric glial cell-driven prognostic model via machine learning predicts survival, recurrence, and therapy response","authors":"Quan Wang , Jinsheng Huang , Shichao Wu , Jintian Wang , Tingting Yu , Wei Wei , Tao Yang , Xuelei Wu , Jianning Zhai , Xiaopeng Zhang","doi":"10.1016/j.yexcr.2025.114733","DOIUrl":"10.1016/j.yexcr.2025.114733","url":null,"abstract":"<div><h3>Background</h3><div>Enteric glial cells (EGCs) have been implicated in colorectal cancer (CRC) progression. This study aimed to develop and validate a prognostic model integrating EGC- and CRC-associated gene expression to predict patient survival, recurrence, metastasis, and therapy response.</div></div><div><h3>Methods</h3><div>Bulk and single-cell RNA sequencing data were analyzed, and a machine learning-based model was constructed using the RSF random forest algorithm. The model's prognostic value was evaluated through survival analysis, pathway enrichment, immune profiling, and therapy response predictions.</div></div><div><h3>Results</h3><div>The model effectively stratified patients into high- and low-risk groups, with high-risk patients exhibiting significantly worse overall survival (OS) and an increased likelihood of recurrence and metastasis. Gene Set Enrichment Analysis (GSEA) identified key pathways associated with tumor progression, immune regulation, and microenvironmental interactions. The model was significantly correlated with immune cell infiltration and chemokine signaling. High-risk patients exhibited reduced immune therapy efficacy and distinct drug sensitivity profiles, suggesting its potential to guide personalized treatment strategies.</div></div><div><h3>Conclusion</h3><div>This model serves as a valuable tool for CRC prognosis and treatment stratification, with potential clinical applications pending further validation.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114733"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiaxing Feng , Mingyang Yang , Rijin Lin , Kaifeng Shang , Meng Sun , Zijie Guo , Yanting Wang , Tianhua Zhou , Feng Yang , Yuehong Yang
{"title":"NudCL2 suppresses pancreatic cancer progression by inhibiting SLC7A11-mediated EMT and metastasis","authors":"Jiaxing Feng , Mingyang Yang , Rijin Lin , Kaifeng Shang , Meng Sun , Zijie Guo , Yanting Wang , Tianhua Zhou , Feng Yang , Yuehong Yang","doi":"10.1016/j.yexcr.2025.114730","DOIUrl":"10.1016/j.yexcr.2025.114730","url":null,"abstract":"<div><div>Pancreatic cancer (PC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. NudC-like protein 2 (NudCL2), a molecular cochaperone of HSP90, has been implicated in various cellular processes; however, its role in pancreatic cancer remains poorly understood. In this study, we report that NudCL2 expression is significantly downregulated in PC tissues and is correlated with poor patient survival. The results of functional assays revealed that NudCL2 knockdown enhances cell invasion and migration <em>in vitro</em> and promotes lung and liver metastases <em>in vivo</em>. Further analysis revealed solute carrier family 7 member 11 (SLC7A11) as a key downstream effector that was upregulated upon NudCL2 depletion. Suppression of SLC7A11 reversed the increase in cell motility induced by NudCL2 depletion. Mechanistically, our findings suggest that NudCL2 regulates the transcriptional activity of SLC7A11 and that the NudCL2/SLC7A11 axis may suppress cell motility by inhibiting the epithelial-mesenchymal transition (EMT) pathway. Collectively, these results highlight the important role of NudCL2 in PC progression through the modulation of EMT via SLC7A11, providing valuable insights into its potential as both a therapeutic target and a prognostic biomarker.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114730"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiang Zhou, Ping Li, Chunyan Li, Qiaoyan Dai, Jian Qi, Yi Yang
{"title":"SOX18 promotes lymphatic vessel regeneration to alleviate lymphedema by upregulating PROX1","authors":"Xiang Zhou, Ping Li, Chunyan Li, Qiaoyan Dai, Jian Qi, Yi Yang","doi":"10.1016/j.yexcr.2025.114743","DOIUrl":"10.1016/j.yexcr.2025.114743","url":null,"abstract":"<div><div>Promoting lymphatic vessel regeneration is an important method for repairing lymphedema. SOX18 can regulate lymphatic vessel development and plays a crucial role in promoting lymphatic vessel generation. This study aims to demonstrate the role of SOX18 in regulating lymphatic vessel regeneration for the repair of lymphedema and explore its related molecular mechanism. We used classical molecular biology methods such as RT-qPCR, Western blotting, CCK8 assay, Transwell assay, immunofluorescence, tube formation assay, dual luciferase assay, and CHIP assay to investigate the role of overexpressed SOX18 in promoting lymphatic vessel regeneration and its related molecular regulatory mechanisms. Subsequently, pathological histological analysis, Western blotting, and immunofluorescence were used to study the lymphedema mouse model. Overexpression of SOX18 promoted the proliferation, migration, and tube formation of LECs <em>in vitro</em>. Overexpression of SOX18 promoted lymphatic vessel regeneration for the repair of lymphedema <em>in vivo</em>. Mechanistically, SOX18 bound to the PROX1 promoter, promoted PROX1 transcription, activated the ERK pathway, upregulated VEGFR3, and promoted lymphatic vessel regeneration. This study demonstrates the important role of overexpressed SOX18 in regulating lymphatic vessel regeneration for the repair of lymphedema, which may provide new therapeutic options for lymphedema treatment.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114743"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shailender Gugalavath , Manas Malla , Atchutha Rao Podilapu , Jee Min Lee , Murali Krishna Voonna , Sanjay V. Malhotra , RamaRao Malla
{"title":"Silencing CD151 gene in donor triple-negative breast cancer cells attenuates exosome-driven functions of recipient cells","authors":"Shailender Gugalavath , Manas Malla , Atchutha Rao Podilapu , Jee Min Lee , Murali Krishna Voonna , Sanjay V. Malhotra , RamaRao Malla","doi":"10.1016/j.yexcr.2025.114740","DOIUrl":"10.1016/j.yexcr.2025.114740","url":null,"abstract":"<div><div>CD151 is a tetraspanin, abnormally expressed in triple negative breast cancer (TNBC). It is a prominent component of exosomes, facilitating the secretion of proteins that promote metastasis and drug resistance. We have previously demonstrated that silencing the CD151 gene reduces metastasis in TNBC. The present study aims to investigate whether silencing the CD151 gene inhibits exosome release and uptake, thereby attenuating donor exosome-mediated functions in recipient cells. Our study found that CD151 expression was negatively correlated with BRCA1 and BRCA2, while it positively correlated with Annexin A2. CD151-positive exosomes were elevated in TNBC cells compared to normal breast epithelial cells. TNBC-derived CD151 exosomes exhibited distinctive structural and phenotypic properties, including expression of CD63 and CD151. They demonstrated functional activities in exosome-cell co-cultures, including the induction of proliferation and mRNA expression of cyclin D1, CDK4, and CDK6 in recipient normal breast, lung, and liver epithelial cells. To further explore the mechanistic role of CD151 in exosome-mediated communication, we isolated iCD151-exosomes and CD151-exosomes from donor TNBC cells with and without CD151 gene silencing, respectively. CD151 exosomes and iCD151 exosomes displayed distinct proteomic profiles, notably Annexin A2 and EGFR, each with specific cellular and molecular functions in vesicle budding and fusion. CD151-exosomes induced a higher migration ability in recipient non-metastatic MCF-7 breast cancer cells and capillary formation by endothelial cells compared to iCD151-exosomes. Additionally, the CD151 exosome induced higher mRNA expression of cyclin D1, CDK4, CDK6, MMP-2, and MMP-9 in MCF-7 cells and VEGF in endothelial cells compared to iCD151 exosomes. These findings demonstrate the potential role of CD151 in orchestrating exosome dynamics for the remodeling of either the adjacent tissue or those in distant organs by transferring metastatic phenotypes from TNBC cells to recipient cells.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114740"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziye Wang, Xiaoguang Li, Zhengdao Liu, Yang Du, Tao Wu
{"title":"LncRNA HANR promotes the aerobic glycolysis in prostate cancer by stabilizing TPI1","authors":"Ziye Wang, Xiaoguang Li, Zhengdao Liu, Yang Du, Tao Wu","doi":"10.1016/j.yexcr.2025.114744","DOIUrl":"10.1016/j.yexcr.2025.114744","url":null,"abstract":"<div><div>Prostate cancer (PCa) is a type of malignancy that originates in the prostate gland, often characterized by uncontrolled cell growth and potential metastasis. Long non-coding RNAs (lncRNAs) play crucial regulatory roles in the progression of prostate cancer, potentially facilitating tumor growth and metastasis via mechanisms that involve the enhancement of aerobic glycolysis. This study aimed to investigate the functional role of lncRNA HANR in prostate cancer progression. Bioinformatics analysis and experimental validation revealed a significant up-regalation of HANR in prostate cancer tissues, in comparison to adjacent normal tissues. Functional studies demonstrated that silencing HANR inhibited prostate cancer cells proliferation, migration, invasion, and glycolysis. While HANR overexpression promoted prostate cancer cells proliferation, invasion, and glycolysis. Mechanistically, HANR interacts with triosephosphate isomerase 1 (TPI1), a key glycolytic enzyme, to promote glycolysis and tumor growth. Silencing HANR or TPI1 reduced prostate tumor growth both <em>in vitro</em> and <em>in vivo</em>. In conclusion, our findings suggest that the HANR-TPI1 axis plays a crucial role in the progression of prostate cancer and may represent a novel biomarker and therapeutic target for aggressive prostate cancer, given its role in enhancing aerobic glycolysis and facilitating tumorigenesis in prostate cancer cells.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114744"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Promoter architecture and enhancer-driven regulation of Cdh1 during MET","authors":"Neslihan Toyran , Hani Alotaibi","doi":"10.1016/j.yexcr.2025.114748","DOIUrl":"10.1016/j.yexcr.2025.114748","url":null,"abstract":"<div><div>E-cadherin (Cdh1) reactivation is a hallmark of the mesenchymal-to-epithelial transition (MET); however, the direct regulatory mechanisms controlling Cdh1 promoter activity remain incompletely understood. Here, we systematically analyzed the responsiveness of the Cdh1 promoter to MET-associated transcription factors using luciferase reporter assays and chromatin immunoprecipitation. An extended Cdh1 promoter fragment exhibited strong basal activity but limited modulation during EMT or MET. Promoter truncation modestly increased basal activity but was insufficient for robust activation. In contrast, integrating a Grhl3-responsive enhancer dramatically enhanced promoter responsiveness, enabling activation by Grhl3 and cooperative enhancement with Hnf4α. Chromatin immunoprecipitation confirmed Grhl3 enrichment at the Cdh1 promoter region during MET, consistent with the enhanced promoter responsiveness observed upon enhancer integration. These findings demonstrate that the dynamic regulation of Cdh1 expression during epithelial plasticity requires coordinated enhancer-promoter interactions and transcription factor recruitment to overcome intrinsic promoter constraints.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114748"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Changwan Cui , Mengqi Hong , Hainan Zhao , Lei Wang , Ying Yang , Jingyu Wang , Li Sun
{"title":"JPH203 alleviates renal fibrosis via inhibition of serine-related mTORC1 pathway in TGF-β1-induced fibroblasts and UUO mice","authors":"Changwan Cui , Mengqi Hong , Hainan Zhao , Lei Wang , Ying Yang , Jingyu Wang , Li Sun","doi":"10.1016/j.yexcr.2025.114732","DOIUrl":"10.1016/j.yexcr.2025.114732","url":null,"abstract":"<div><div>Renal fibrosis is the common pathological outcome of chronic kidney disease (CKD) progressing into end-stage renal disease. The excessive proliferation of fibroblasts plays an important role in the CKD progression. Nutrients such as amino acids and their transportation are essential for cell proliferation. In this study, TGF-β1-induced fibroblasts and UUO mouse models were used. The target gene solute carrier family 7 member 5 (SLC7A5) was screened to be highly expressed and localized in the renal fibroblasts of CKD mice. In vivo experiments showed that SLC7A5 promoted the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, enhanced serine synthesis and maintained oxidative stress balance in fibroblasts. SLC7A5 increased the expression of transcription factor activating transcription factor 4 (ATF4), promoted the transcription of serine de-novo synthesis enzyme PHGDH, and increased the synthesis of glutathione, a byproduct of serine synthesis pathway. JPH203, a specific inhibitor of SLC7A5, effectively reversed the above phenomena, inhibited mTORC1 signaling activation, and reduced the proliferation of fibroblasts. The efficacy of JPH203 was further verified by in vivo experiments. JPH203 had a similar effect to the inhibitory adenovirus AV-shSLC7A5 in the UUO mouse model. Compared with the UUO group, the activation of mTORC1 pathway in the JPH203 treatment group was inhibited, and the expressions of α-SMA and vimentin in fibroblasts were decreased. The fibrotic state of renal tissues was effectively relieved. In addition, the levels of serum creatinine, blood urea nitrogen and pelvic urinary protein were significantly decreased compared with the UUO group. In conclusion, our study demonstrated that JPH203 can alleviate renal fibrosis via inhibition of serine-related mTORC1 pathway in fibroblasts in UUO mice. These results may provide a theoretical foundation for the pathogenesis of renal fibrosis and a novel therapeutic strategy for CKD.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114732"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}