International Journal of Biological Sciences最新文献

{"title":"Celastrol-Based Hybrid Prodrug Ameliorates ALI by Spatiotemporally Consecutive Dual-Targeting GLUT1/Drp1 to Reestablish Mitochondrial Homeostasis.","authors":"Hong Xu, Hongyu Chen, Fengling He, Xinlan Li, Wanxin Li, Qingqing Yang, Tingting Zhang, Jin Liu, Xiaoke Shi, Shilin Chen, Defang Li, Jun Lu","doi":"10.7150/ijbs.133756","DOIUrl":"10.7150/ijbs.133756","url":null,"abstract":"<p><p>Aberrant activation of macrophages and their amplification of inflammatory responses constitute the core pathological basis driving the progression of acute lung injury (ALI). Celastrol (CE), despite its potent anti-inflammatory activity, suffers from poor aqueous solubility and substantial systemic toxicity, which severely limit its clinical translation. Capitalizing on the metabolic signature of pro-inflammatory M1 macrophages, specifically their high expression of glucose transporter 1 (GLUT1), we designed a glucose-modified CE prodrug that self-assembled into carrier-free nanoparticles CG NPs. With markedly improved solubility and systemic stability, CG NPs rapidly and persistently accumulated in the inflammatory lungs of LPS-induced ALI mice facilitated by GLUT1-mediated targeting and uptake by M1 macrophages. Compared with free CE, CG NPs exhibited enhanced overall therapeutic efficacy while significantly reducing hepatorenal toxicity. Mechanistic studies revealed that by targeting Drp1, CG NPs disrupt Drp1-MiD51 interaction, thus inhibiting excessive mitochondrial fission and ROS accumulation, which blocks NF-κB-mediated inflammatory signaling and M1-driven cytokine release. Molecular docking suggested that glucose conjugation may confer CG with a superior ability to regulate mitochondrial homeostasis over CE, potentially driven by its unique U-shaped conformation that inserts into Drp1 and forms a denser hydrogen-bond network, which could contribute to enhanced binding affinity. In summary, this study proposes a nanoprodrug strategy that combines precise targeting with mitochondrial protection, offering a promising therapeutic avenue for inflammatory diseases such as ALI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7427-7446"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887087","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 Acidic Exosomal miR-1246/WASF3 Axis Regulates Hepatic Stellate Cell Activation and Stiff ECM Remodeling to Promote Pancreatic Ductal Adenocarcinoma Liver Metastasis.","authors":"Dongqi Li, Xiangyu Chu, Fusheng Zhang, Yongsu Ma, Weikang Liu, Ping Li, Xiaocui Fang, Chen Wang, Xiaodong Tian, Yanlian Yang, Yinmo Yang","doi":"10.7150/ijbs.132772","DOIUrl":"10.7150/ijbs.132772","url":null,"abstract":"<p><p>Liver metastasis is a major factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). The formation of pre-metastatic niche (PMN) initiates the process of liver metastasis. Exosomes (Exos) act as key mediators of crosstalk between the tumor microenvironment (TME) and the PMN to activate hepatic stellate cells (HSCs) and remodel the stiff extracellular matrix (ECM). In this study, we isolated Exos derived from PDAC cells cultured under acidic conditions and demonstrated that these Exos significantly activate HSCs and promote the remodeling of the stiff ECM, thereby promoting the stemness, migration, and invasion of PDAC cells. High expression of exosomal miR-1246 was screened by miRNA-sequencing, and Wiskott-Aldrich syndrome protein Family Member 3 (WASF3) was identified as the target of miR-1246. Mechanistically, exosomal miR-1246 activates HSCs to remodel the ECM by targeting WASF3 and stimulating the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K/Akt) pathway. Notably, RNA-binding protein immunoprecipitation (RIP) and miRNA pull-down assays were performed to identify that Human Antigen R (HuR) contributes to the enrichment of miR-1246 into Exos. Collectively, exosomal miR-1246 activates HSCs and remodels the stiff ECM to promote liver metastasis, and it may serve as a potential diagnostic and prognostic marker for PDAC liver metastasis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7358-7379"},"PeriodicalIF":11.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887318","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 Triad of NF-κB, HIF-1α, and Oxidative Stress in Hepatocellular Carcinoma: Pathogenesis, Clinical Challenges, and Therapeutic Potential of CIGB-552 in Liver Transplantation.","authors":"Xufan Cai, Muqiong Xing, Qianrang Lu, Julio R Fernández Massó, Brizaida Oliva Arguelles, Maidel Carpio Alvarez, Ming Chen, Qi Ling","doi":"10.7150/ijbs.137642","DOIUrl":"10.7150/ijbs.137642","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) represents a formidable oncological challenge characterized by complex molecular pathogenesis and limited therapeutic outcomes, particularly in the context of liver transplantation. As the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide, HCC poses significant clinical challenges that demand innovative therapeutic approaches. Central to HCC development and progression is a pathogenic triad comprising nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and oxidative stress-three interconnected pathways that drive inflammation, angiogenesis, metabolic reprogramming, and cell survival. This comprehensive review examines the molecular mechanisms underlying this triad in HCC pathogenesis across different etiological contexts, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). We critically analyse the unique clinical challenges posed by HCC in liver transplantation recipients, particularly the paradoxical requirement for immunosuppression alongside antitumor immunity, and constraints surrounding immunotherapy application. Furthermore, we present CIGB-552, a novel peptide therapeutic targeting COMMD1 (Copper Metabolism MURR1 Domain-containing protein 1), as a promising dual-function agent capable of simultaneously disrupting the pathogenic triad through NF-κB inhibition, HIF-1α suppression, and strategic modulation of oxidative stress via SOD1 regulation. The multimodal mechanism of CIGB-552 offers a theoretically rational therapeutic approach for HCC management in both pre-transplant and post-transplant settings. Clinical validation in the transplantation setting is required.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7316-7331"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886725","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 Role of Biomechanical Regulation in Physiological and Pathological Pregnancy: From Mechanotransduction to Clinical Implications.","authors":"Tingting Wang, Wanru Chen, Huixia Yang, Jie Yan","doi":"10.7150/ijbs.134599","DOIUrl":"10.7150/ijbs.134599","url":null,"abstract":"<p><p>Pregnancy is a highly coordinated process that relies on the precise regulation of the extracellular matrix, cells, and various molecules at the maternal-fetal interface. As the fetus grows and amniotic fluid increases, the uterus undergoes adaptive remodeling, a process in which biomechanics plays an indispensable role. This review aims to systematically explore the biomechanical characteristics of the uterus and specifically elucidate the crucial regulatory roles of mechanical signals such as stiffness, shear stress, tension, and compression force in both physiological and pathological pregnancies. We focus on the remodeling of the extracellular matrix, the mechanical property changes of the maternal-fetal interface, and the associated mechanotransduction pathways, such as PIEZO1, integrins, and YAP/TAZ. Finally, we summarize the cutting-edge technologies used to investigate uterine biomechanics and discuss the clinical translational potential of targeting mechanical signaling pathways as novel diagnostic and therapeutic strategies for pregnancy complications. This review provides a comprehensive analysis of how biomechanical cues regulate uterine function at the molecular, cellular, and tissue levels.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7240-7258"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887314","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":"Chlorogenic acid promotes mtDNA leakage to enhance cGAS-STING induced anti-tumor immunity via ATF5-mtHSP70-TFAM system.","authors":"Rui Li, Ping Zhou, Chu-Juan Hu, Ge Si, Ling Ren, Jin-Jin Cui, Ying-Ying He, Yan-Xing Han, Jie Zhang, Wen-Bin Li, Lu-Lu Wang, Jian-Dong Jiang","doi":"10.7150/ijbs.136878","DOIUrl":"10.7150/ijbs.136878","url":null,"abstract":"<p><p>Mitochondrial targeting represents a promising antitumor strategy by modulating cell differentiation, metabolic reprogramming, and immune responses. While chlorogenic acid (CGA) has demonstrated the ability to induce tumor cell differentiation and enhance antitumor immunity, the involvement of mitochondrial regulation in these effects remains unclear. This study investigated whether CGA mediates antitumor immune effects through mitochondrial regulation, thereby providing a theoretical framework for natural product-based, mitochondria-targeted therapies. Our findings reveal that CGA inhibits the translocation of mitochondrial transcription factor A (TFAM) into the mitochondria and promotes mtDNA leakage by disrupting the ATF5-mtHSP70 signaling axis. The cytosolic leakage of mtDNA activates the cGAS/STING pathway, triggering the activation of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), which ultimately facilitates antitumor immunity. In a mouse model, ATF5 knockout enhances cGAS/STING signaling and subsequent immune responses, leading to tumor growth inhibition. These results highlight a novel role of CGA in regulating mitochondrial-associated proteins, positioning it as a potential therapeutic strategy for cancer via the mtDNA-cGAS-STING pathway.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7277-7294"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887090","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 Role of Distinct Cancer-Associated Fibroblast Subtypes in Prostate Cancer Immunotherapy.","authors":"Kankan He, Zhite Zhao, Jianhui Bai, Tong Lu, Yaohua Hu, Xinglin He, Fanchao Wei, Yixin Zhang, Yanan Gu, Zhaokun Shi, Xiangliang Meng, Fuli Wang, Changhong Shi, Weijun Qin, Keying Zhang, Qiaoli Xie, Lijun Yang","doi":"10.7150/ijbs.132227","DOIUrl":"10.7150/ijbs.132227","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have achieved breakthroughs in various solid tumors; however, their efficacy remains limited in prostate cancer (PCa), which is closely associated with its highly immunosuppressive tumor microenvironment (TME). As the most abundant stromal component in the TME, cancer-associated fibroblasts (CAFs) exhibit remarkable heterogeneity and functional plasticity, playing a central role in orchestrating an immunologically \"cold\" tumor phenotype and driving resistance to immunotherapy. We have moved beyond simple marker-based classification of cancer-associated fibroblast (CAF) subtypes - a framework still widely used in routine pathological assessment - and now define these populations by their functional states and molecular profiles, enabled by advances in single-cell sequencing, spatial multi-omics, and computational biology. Such functional divergence across stromal subsets allows individual CAF populations to engage in complex, multilayered crosstalk with different immune cell types, and together they build an immunosuppressive network that drives tumor immune evasion. This review systematically catalogs the identification methods and signature gene panels for distinct CAF subtypes in prostate cancer, with particular focus on the multilayered regulatory circuits through which these stromal cells shape the immune microenvironment. We also highlight emerging CAF-targeted strategies designed to reverse immunosuppressive states. This integrated perspective frames CAF heterogeneity in prostate cancer immune evasion, and establishes theoretical underpinnings and translational pathways for next-generation precision combination immunotherapies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7259-7276"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887328","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":"Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.","authors":"Hao Lu, Shenyu Yan, Baoyi Shao, Jianbo Guo, Yifan Wang, Rui Hou, Shen Chen, Meicen Wu, Biao Wei, Fei Li, Xiaoming Meng, Haiyong Chen","doi":"10.7150/ijbs.138435","DOIUrl":"10.7150/ijbs.138435","url":null,"abstract":"<p><p>Mitochondrial homeostasis has attracted increasing interest and is now recognized as playing a significant role in both kidney development and the progression of kidney disease. Among these, the latest approach, mitophagy, has been shown to be activated dynamically and reversibly under various physiological conditions, including reactive oxygen stress, nutrient deficiency, and cellular senescence, to maintain mitochondrial homeostasis and function. Moreover, findings indicate that mitophagy can also maintain mitochondrial quality through interactions and mutual regulation with mitochondrial dynamics. Crucially, a growing number of kidney diseases, such as acute kidney injury, diabetic kidney disease, and other chronic kidney diseases, are linked to abnormal levels of mitophagy. In this review, we comprehensively examined the vital role of mitophagy in kidney diseases, discussed the potential of mitophagy-targeted therapies, and described the detailed alterations in specific mitophagy-related proteins associated with kidney diseases.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7332-7348"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887116","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":"piRNA-46403 Promotes Sertoli Cell Ferroptosis via Disrupting m5C-dependent USP18 mRNA Stabilization in Varicocele-mediated Infertility.","authors":"Xiao Fang, Li Song, Dong Liu, Zhixiang Xin, Wenjuan Pang, Qiang Tong, Jing Huang, Anbang Wang, Lei Yin, Hejing Huang, Aimin Jiang, Shancheng Ren","doi":"10.7150/ijbs.137298","DOIUrl":"10.7150/ijbs.137298","url":null,"abstract":"<p><p>Varicocele (VC) represents a primary etiology of male infertility, yet the epigenetic landscapes and molecular triggers driving VC-associated spermatogenic failure remain largely enigmatic. Herein, it is demonstrated that Sertoli cell ferroptosis is a critical pathological feature of VC, and its pharmacological inhibition effectively rescues VC-induced reproductive impairment <i>in vivo</i>. Through small RNA sequencing of clinical testicular tissues, piRNA-46403 is identified as a significantly upregulated mediator in VC patients with asthenospermia. Functionally, piRNA-46403 is shown to orchestrate Sertoli cell ferroptosis, whereas its silencing attenuates spermatogonial apoptosis and restores spermatogenic function. Mechanistically, piRNA-46403 acts as a molecular decoy that binds to the RNA-binding protein YBX1. This interaction disrupts the binding of YBX1 to m5C-modified USP18 mRNA, thereby reducing USP18 mRNA stability and triggering ferroptosis. These findings elucidate a novel piRNA-46403/YBX1/m5C-modified USP18 regulatory axis in the male reproductive system and position piRNA-46403 as a promising therapeutic target for mitigating VC-mediated infertility.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7295-7315"},"PeriodicalIF":11.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887098","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":"From Cysteamine to Pepstatin A: Targeting Cathepsin D To Improve Bone Health in Cystinosis.","authors":"Giulia Battafarano, Michela Rossi, Olivia Pagliarosi, Laura Di Giuseppe, Jacopo Di Gregorio, Sara Terreri, Cristiano De Stefanis, Marco Pezzullo, Gianna Di Giovamberardino, Pamela Vernocchi, Valeria Marzano, Lorenza Putignani, Jessica D'Amico, Fiorella Piemonte, Anna Taranta, Francesco Emma, Andrea Del Fattore","doi":"10.7150/ijbs.135791","DOIUrl":"10.7150/ijbs.135791","url":null,"abstract":"<p><p>Nephropathic cystinosis is a rare genetic lysosomal storage disorder caused by <i>loss-of-function</i> variants of the <i>CTNS</i> gene encoding for the lysosomal H⁺/cystine symporter cystinosin. The lack of cystinosin causes cystine accumulation in lysosomes and cell damage. Children with nephropathic cystinosis commonly exhibit skeletal abnormalities, including growth retardation, osteopenia and rickets. The only cystine-depleting drug available is cysteamine. However, several observations suggest that cysteamine, particularly at high doses, may have negative effects on the skeleton. In this study, we characterized the effects of cysteamine on bone cells and we identified Pepstatin A, a Cathepsin D-inhibitor, as a potential new therapeutic treatment to restore physiological bone remodeling in cystinosis. We observed a detrimental effect of cysteamine on bone cells inducing further impairment of osteoblast differentiation/activity and failure of cysteamine intraperitoneal injection to improve the somatic growth of pre-pubertal <i>ctns^-/-</i> mice. Moreover, we demonstrated that Pepstatin A treatment increased bone formation <i>in vitro</i> acting on the Fibronectin/Sipa1/STAT3/JunB pathway, and rescued somatic growth and bone mass in pre-pubertal <i>ctns^-/-</i> mice. Our results provide evidence that cysteamine negatively affects bone in cystinosis and that Cathepsin D inhibition could represent a new therapeutic approach for rescue of bone remodeling in cystinosis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7209-7224"},"PeriodicalIF":11.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887124","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":"Targeting the heparan sulfate proteoglycan/heparanase axis as a novel therapeutic strategy to drive adipogenesis and block tumor growth of dedifferentiated liposarcoma.","authors":"Cinzia Lanzi, Enrica Favini, Laura Dal Bo, Monica Tortoreto, Stefano Percio, Valentina Zuco, Gian Paolo Dagrada, Silvia Brich, Paola Collini, Loris De Cecco, Dario Callegaro, Roberta Sanfilippo, Alessandro Gronchi, Nadia Zaffaroni, Yehuda G Assaraf, Sandro Pasquali, Giuliana Cassinelli","doi":"10.7150/ijbs.133802","DOIUrl":"10.7150/ijbs.133802","url":null,"abstract":"<p><p>Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal malignancy coexisting with a low grade well-differentiated component. Pathways implicated in liposarcoma growth and dedifferentiation are promoted by heparan sulfate (HS) proteoglycans (HSPG) and their modifying enzymes including heparanase. HSPGs serve as co-receptors enhancing tyrosine kinase signaling and tumor aggressiveness. Targeting these interactions bears promise in attenuating liposarcoma growth. We employed an investigational HS mimetic, the non-anticoagulant heparin CX-01 (dociparstat), to assess its HS competition impact on deregulated adipogenic differentiation and growth of human DDLPS cell lines and patient-derived xenografts (PDXs). Remarkably, CX-01 reduced colony formation and invasive capacities of DDLPS cell lines, inducing cytoskeleton remodeling, lipid accumulation and reactivation of adipogenic program. Mechanistic studies into the anti-DDLPS activity of CX-01 unveiled Syndecan 1 (SDC1)/heparanase system and receptor tyrosine kinase-AKT signaling as targets of cell growth inhibition and induction of differentiation. CX-01 treatment of mice harboring DDLPS PDXs attenuated tumor growth, enhanced lipid content and consistently altered the transcriptome, modulating pathways associated with tumor dedifferentiation (adipogenesis and fatty acid metabolism) and tumor-microenvironment interaction (TGFβ signaling, inflammatory response). In two independent cohorts of DDLPS patients, genes downregulated in CX-01-treated PDXs (SDC1, TIMP1, FN1, COL5A1, and MMP14), were found preeminently expressed in the dedifferentiated, compared to the well-differentiated tumor component and normal fat. This suggests a role for these genes in disease progression. Collectively, this study demonstrates the remarkable potential of HS competition to simultaneously block multiple anti-adipogenic players representing metabolic vulnerabilities, and to promote a differentiated tumor phenotype markedly less aggressive.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"22 13","pages":"7173-7190"},"PeriodicalIF":11.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887191","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}