ACS Pharmacology and Translational Science最新文献

{"title":"Discovery of a Novel, Potent, and Selective 5-Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney","authors":"Paul Victor Santiago Raj,&nbsp;Giri Gnawali,&nbsp;Jaroslav Janda,&nbsp;Natalie E. Scholpa,&nbsp;Vishal Kaleeswaran,&nbsp;Ishika Girdhar,&nbsp;Wei Wang and Rick G. Schnellmann*,&nbsp;","doi":"10.1021/acsptsci.5c0016110.1021/acsptsci.5c00161","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00161https://doi.org/10.1021/acsptsci.5c00161","url":null,"abstract":"<p >Serotonin, or 5-hydroxytryptamine (5-HT), is a multifaceted neurotransmitter that plays a vital role in the central nervous system (CNS). Beyond the CNS, 5-HT is intricately involved in modulating hemostasis, immune response, blood pressure, and metabolism in tissues such as skeletal muscle, heart, and kidney. Accumulating evidence highlights the interplay between 5-HT receptors and mitochondrial bioenergetics. Here, we report the discovery of a novel, potent, and selective 5-hydroxytryptamine 2B receptor (5-HT_2BR) antagonist, <b>MARY1,</b> which induces mitochondrial biogenesis (MB) in the kidney. <b>MARY1</b> is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (<i>K</i>_i = 764 nM) for the human 5-HT_2BR, as well as efficacy (IC₅₀ = 380 nM; <i>E</i>_max = 90%) in cellular-based binding and functional assays. Treatment with <b>MARY1</b> (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of <b>MARY1</b> in RPTCs are mediated through 5-HT_2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, <b>MARY1</b> administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify <b>MARY1</b> as a selective and potent 5-HT_2BR antagonist that induces MB and enhances mitochondrial function in the kidney, offering a potential therapeutic strategy for metabolic and mitochondrial dysfunction-associated renal disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1741–1755 1741–1755"},"PeriodicalIF":4.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling for Iron-Regulated Hematopoietic Stem and Progenitor Cells’ Commitment toward Erythroid and Megakaryocytic Lineages","authors":"Kangna Cao,&nbsp;Xiaoqing Fan,&nbsp;Raymond S. M. Wong and Xiaoyu Yan*,&nbsp;","doi":"10.1021/acsptsci.5c0009710.1021/acsptsci.5c00097","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00097https://doi.org/10.1021/acsptsci.5c00097","url":null,"abstract":"<p >Iron replenishment is a cornerstone therapy for anemia in diverse diseases. While its role in erythrocyte hemoglobinization is well-established, the broader impact of iron on other aspects of hematopoiesis, such as thrombopoiesis, remains poorly understood. In this study, we demonstrate that iron plays a regulatory role in the commitment of hematopoietic stem and progenitor cells (HSPCs) toward erythroid and megakaryocytic lineages. Using colony-forming unit assays and flow cytometry, we observed that iron increases the proportion of erythroid cells while reducing the proportion of megakaryocytic cells. Transcriptomic profiling and functional output analyses identified the MAPK/ERK pathway as a critical mediator of iron-regulated HSPCs’ commitment. Corroborating <i>in vitro</i> findings, rats with iron deficiency anemia exhibited continuously elevated platelets and decreased red blood cell counts, while intravenous iron supplementation reversed these effects. This effect of iron was enhanced in combination with erythropoietin, a key cytokine in erythropoiesis. A mechanism-based pharmacokinetic/pharmacodynamic model was developed to quantify the impact of iron on the two lineages. The dynamic interplay between iron levels and the development of erythropoiesis and thrombopoiesis was accurately recapitulated in rats. The model was further extrapolated to humans and validated with clinical data. Overall, this work not only provides functional insights into the pivotal role of iron in erythropoiesis and thrombopoiesis but also holds translational implications for optimizing iron therapy in anemia and potentially other hematologic conditions where erythropoiesis and thrombopoiesis are affected.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1711–1725 1711–1725"},"PeriodicalIF":4.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00097","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.","authors":"Paul Victor Santiago Raj, Giri Gnawali, Jaroslav Janda, Natalie E Scholpa, Vishal Kaleeswaran, Ishika Girdhar, Wei Wang, Rick G Schnellmann","doi":"10.1021/acsptsci.5c00161","DOIUrl":"10.1021/acsptsci.5c00161","url":null,"abstract":"<p><p>Serotonin, or 5-hydroxytryptamine (5-HT), is a multifaceted neurotransmitter that plays a vital role in the central nervous system (CNS). Beyond the CNS, 5-HT is intricately involved in modulating hemostasis, immune response, blood pressure, and metabolism in tissues such as skeletal muscle, heart, and kidney. Accumulating evidence highlights the interplay between 5-HT receptors and mitochondrial bioenergetics. Here, we report the discovery of a novel, potent, and selective 5-hydroxytryptamine 2B receptor (5-HT_2BR) antagonist, <b>MARY1,</b> which induces mitochondrial biogenesis (MB) in the kidney. <b>MARY1</b> is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (<i>K</i> _i = 764 nM) for the human 5-HT_2BR, as well as efficacy (IC₅₀ = 380 nM; <i>E</i> _max = 90%) in cellular-based binding and functional assays. Treatment with <b>MARY1</b> (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of <b>MARY1</b> in RPTCs are mediated through 5-HT_2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, <b>MARY1</b> administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify <b>MARY1</b> as a selective and potent 5-HT_2BR antagonist that induces MB and enhances mitochondrial function in the kidney, offering a potential therapeutic strategy for metabolic and mitochondrial dysfunction-associated renal disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1741-1755"},"PeriodicalIF":4.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Selective Serotonin 5‑HT_2A Receptor Agonist (<i>S</i>)‑3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents.","authors":"Anders A Jensen, Claudia R Cecchi, Meghan Hibicke, Astrid H Bach, Erik Kaadt, Emil Märcher-Rørsted, Charles D Nichols, Betina Elfving, Jesper L Kristensen","doi":"10.1021/acsptsci.5c00208","DOIUrl":"10.1021/acsptsci.5c00208","url":null,"abstract":"<p><p>Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(<i>S</i>)-3-(2,5-dimethoxy-4-(trifluoromethyl)-phenyl)-piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT_2A receptor (5-HT_2AR) with pronounced selectivity for 5-HT_2AR over the related 5-HT_2BR and 5-HT_2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT_2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1791-1803"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents","authors":"Anders A. Jensen,&nbsp;Claudia R. Cecchi,&nbsp;Meghan Hibicke,&nbsp;Astrid H. Bach,&nbsp;Erik Kaadt,&nbsp;Emil Märcher-Rørsted,&nbsp;Charles D. Nichols,&nbsp;Betina Elfving and Jesper L. Kristensen*,&nbsp;","doi":"10.1021/acsptsci.5c0020810.1021/acsptsci.5c00208","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00208https://doi.org/10.1021/acsptsci.5c00208","url":null,"abstract":"<p >Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(<i>S</i>)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT_2A receptor (5-HT_2AR) with pronounced selectivity for 5-HT_2AR over the related 5-HT_2BR and 5-HT_2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT_2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1791–1803 1791–1803"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis.","authors":"Qi-Xin Guan, Long-Bo Yu, Peng Wang, Qing-Yuan Hu, Cai-Ping Tan","doi":"10.1021/acsptsci.5c00219","DOIUrl":"10.1021/acsptsci.5c00219","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (<b>Ti-DFX-TPP</b>) to disrupt iron homeostasis in TNBC cells through transmetalation. <b>Ti-DFX-TPP</b> depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by <b>Ti-DFX-TPP</b> increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that <b>Ti-DFX-TPP</b> inhibits tumor growth without significant toxicity to major organs. These findings suggest that <b>Ti-DFX-TPP</b> is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1804-1813"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modernizing Preclinical Drug Development: The Role of New Approach Methodologies","authors":"Krina Mehta*,&nbsp;Christian Maass,&nbsp;Lourdes Cucurull-Sanchez,&nbsp;Cesar Pichardo-Almarza,&nbsp;Kalyanasundaram Subramanian,&nbsp;Ioannis P. Androulakis,&nbsp;Jogarao Gobburu,&nbsp;Stephan Schaller and Catherine M Sherwin,&nbsp;","doi":"10.1021/acsptsci.5c0016210.1021/acsptsci.5c00162","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00162https://doi.org/10.1021/acsptsci.5c00162","url":null,"abstract":"<p >Over 90% of investigational drugs fail during clinical development, largely due to poor translation of pharmacokinetic, efficacy, and toxicity data from preclinical to clinical settings. The high costs and ethical concerns associated with translational failures highlight the need for more efficient and reliable preclinical tools. Human-relevant new approach methodologies (NAMs), including advanced in vitro systems, in silico mechanistic models, and computational techniques like artificial intelligence and machine learning, can improve translational success, as evident by several literature examples. Case studies on physiologically based pharmacokinetic modeling and quantitative systems pharmacology applications demonstrate the potential of NAMs in improving translational accuracy, reducing reliance on animal studies. Additionally, mechanistic modeling approaches for drug-induced liver injury and tumor microenvironment models have provided critical insights into drug safety and efficacy. We propose a structured and iterative “a priori in silico” workflow that integrates NAM components to actively guide preclinical study design─a step toward more predictive and resource-efficient drug development. The proposed workflow can enable in vivo predictions to guide the design of reduced and optimal preclinical studies. The findings from these preclinical studies can then be used to refine computational models to enhance the accuracy of human predictions or guide additional preclinical studies, as needed. To conclude, integrating computational and in vitro NAM approaches can optimize preclinical drug development, improving translational accuracy and reducing clinical trial failures. This paradigm shift is further supported by global regulations, such as the FDA Modernization Act 2.0 and EMA directive 2010/63/EU, underscoring the regulatory momentum toward adopting human-relevant NAMs as the new standard in preclinical drug development.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1513–1525 1513–1525"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Tuning of Cyanine 5 Dyes to Improve the Pharmacokinetic Profile of Nanobody-Based Fluorescent Tracers","authors":"Łukasz Mateusiak*,&nbsp;Dora M. Chigoho,&nbsp;Sam Floru,&nbsp;Sofie Pollenus,&nbsp;Pieterjan Debie,&nbsp;Danny M. van Willigen,&nbsp;Fijs W. B. van Leeuwen and Sophie Hernot*,&nbsp;","doi":"10.1021/acsptsci.5c0002410.1021/acsptsci.5c00024","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00024https://doi.org/10.1021/acsptsci.5c00024","url":null,"abstract":"<p >Over the past two decades, it has become evident that fluorescence imaging holds substantial value in preclinical research and could also play a pivotal role in clinical applications such as intraoperative molecular imaging. The latter relies on applying targeted fluorescent agents designed to recognize specific biomarkers expressed in diseased tissues. Targeting moieties, such as camelid-derived nanobodies (Nbs), exhibit remarkable pharmacokinetics for molecular imaging owing to their robustness and compact size. However, the relatively small size of Nbs makes their pharmacokinetics sensitive to the chemical structure of attached fluorophores. In this study, we conducted a comparative analysis between Nbs labeled with three different sulfoCy5 derivatives (Cy5^2– (charge −2), Cy5^– (charge −1), and Cy5° (charge 0)). Nb-Cy5^2– and Nb-Cy5° allowed specific <i>in vivo</i> visualization of subcutaneous tumors in mice within 1 h with minimal background. Conversely, Nb-Cy5^– required at least 3 h to achieve sufficient contrast and exhibited nonspecific liver accumulation. Remarkably, Nb-Cy5^2– was able to overcome the renal retention typically observed for Nbs. Microscopy analyses of kidney sections revealed differential accumulation for Nb-Cy5^2– and Nb-Cy5° at the level of the proximal tubule cells, with only Nb-Cy5^2– showing internalization in lysosomes and endosomes and subsequent metabolization. In conclusion, this study underscores the significant influence of dye charges on the biodistribution profile and tumor-targeting capabilities of Nb tracers. Among the tested variants, the fluorescent dye Cy5^2– emerged as a promising choice to use in combination with Nbs for molecular imaging applications, in particular due to its low renal retention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1659–1668 1659–1668"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Tuning of Cyanine 5 Dyes to Improve the Pharmacokinetic Profile of Nanobody-Based Fluorescent Tracers.","authors":"Łukasz Mateusiak, Dora M Chigoho, Sam Floru, Sofie Pollenus, Pieterjan Debie, Danny M van Willigen, Fijs W B van Leeuwen, Sophie Hernot","doi":"10.1021/acsptsci.5c00024","DOIUrl":"10.1021/acsptsci.5c00024","url":null,"abstract":"<p><p>Over the past two decades, it has become evident that fluorescence imaging holds substantial value in preclinical research and could also play a pivotal role in clinical applications such as intraoperative molecular imaging. The latter relies on applying targeted fluorescent agents designed to recognize specific biomarkers expressed in diseased tissues. Targeting moieties, such as camelid-derived nanobodies (Nbs), exhibit remarkable pharmacokinetics for molecular imaging owing to their robustness and compact size. However, the relatively small size of Nbs makes their pharmacokinetics sensitive to the chemical structure of attached fluorophores. In this study, we conducted a comparative analysis between Nbs labeled with three different sulfoCy5 derivatives (Cy5^2- (charge -2), Cy5^- (charge -1), and Cy5° (charge 0)). Nb-Cy5^2- and Nb-Cy5° allowed specific <i>in vivo</i> visualization of subcutaneous tumors in mice within 1 h with minimal background. Conversely, Nb-Cy5^- required at least 3 h to achieve sufficient contrast and exhibited nonspecific liver accumulation. Remarkably, Nb-Cy5^2- was able to overcome the renal retention typically observed for Nbs. Microscopy analyses of kidney sections revealed differential accumulation for Nb-Cy5^2- and Nb-Cy5° at the level of the proximal tubule cells, with only Nb-Cy5^2- showing internalization in lysosomes and endosomes and subsequent metabolization. In conclusion, this study underscores the significant influence of dye charges on the biodistribution profile and tumor-targeting capabilities of Nb tracers. Among the tested variants, the fluorescent dye Cy5^2- emerged as a promising choice to use in combination with Nbs for molecular imaging applications, in particular due to its low renal retention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1659-1668"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis","authors":"Qi-Xin Guan,&nbsp;Long-Bo Yu,&nbsp;Peng Wang,&nbsp;Qing-yuan Hu* and Cai-Ping Tan*,&nbsp;","doi":"10.1021/acsptsci.5c0021910.1021/acsptsci.5c00219","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00219https://doi.org/10.1021/acsptsci.5c00219","url":null,"abstract":"<p >Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (<b>Ti-DFX-TPP</b>) to disrupt iron homeostasis in TNBC cells through transmetalation. <b>Ti-DFX-TPP</b> depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by <b>Ti-DFX-TPP</b> increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that <b>Ti-DFX-TPP</b> inhibits tumor growth without significant toxicity to major organs. These findings suggest that <b>Ti-DFX-TPP</b> is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1804–1813 1804–1813"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}