Pub Date : 2025-10-28DOI: 10.1016/j.pharmthera.2025.108942
Peter Holzer
{"title":"Editorial: Beyond the opioid crisis: New targets for the management of chronic pain","authors":"Peter Holzer","doi":"10.1016/j.pharmthera.2025.108942","DOIUrl":"10.1016/j.pharmthera.2025.108942","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"276 ","pages":"Article 108942"},"PeriodicalIF":12.5,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-27DOI: 10.1016/j.pharmthera.2025.108943
Eric A. Okrah , Claire Allan , Monika S. Doblin , Sarah J. Annesley
Cannabidiol (CBD) is one of the major active constituents among the several hundreds of compounds found in the cannabis plant. It is a non-psychoactive compound known for its anti-inflammatory, neuroprotective, antidepressant and anxiolytic effects. In preclinical studies it has shown to be effective, safe, and well-tolerated in mitigating the symptoms associated with Parkinson's disease (PD) and other neurodegenerative diseases. However, the mechanism of action is not fully characterised. CBD is postulated to exert its therapeutic effects through its interaction with the endocannabinoid system (ECS), and via interaction with a large array of non-cannabinoid receptors, neurotransmitters, and enzymes. These interactions are complex and are influenced by cell type, concentration and exposure time. The lack of specificity for a single receptor system makes CBD an intriguing therapeutic compound and enables it to influence multiple pathways. This broad interaction goes beyond its beneficial therapeutic effects and could lead to potential adverse effects. Detailed understanding of the versatility and complexity of how CBD exerts its effect is required so that the true potential as a therapeutic option can be realised.
{"title":"Cannabidiol and Parkinson's disease: Investigating receptor interactions and their therapeutic implications","authors":"Eric A. Okrah , Claire Allan , Monika S. Doblin , Sarah J. Annesley","doi":"10.1016/j.pharmthera.2025.108943","DOIUrl":"10.1016/j.pharmthera.2025.108943","url":null,"abstract":"<div><div>Cannabidiol (CBD) is one of the major active constituents among the several hundreds of compounds found in the cannabis plant. It is a non-psychoactive compound known for its anti-inflammatory, neuroprotective, antidepressant and anxiolytic effects. In preclinical studies it has shown to be effective, safe, and well-tolerated in mitigating the symptoms associated with Parkinson's disease (PD) and other neurodegenerative diseases. However, the mechanism of action is not fully characterised. CBD is postulated to exert its therapeutic effects through its interaction with the endocannabinoid system (ECS), and via interaction with a large array of non-cannabinoid receptors, neurotransmitters, and enzymes. These interactions are complex and are influenced by cell type, concentration and exposure time. The lack of specificity for a single receptor system makes CBD an intriguing therapeutic compound and enables it to influence multiple pathways. This broad interaction goes beyond its beneficial therapeutic effects and could lead to potential adverse effects. Detailed understanding of the versatility and complexity of how CBD exerts its effect is required so that the true potential as a therapeutic option can be realised.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"277 ","pages":"Article 108943"},"PeriodicalIF":12.5,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oxylipins are oxygenated bioactive lipid mediators formed from different polyunsaturated fatty acids through the bioactions of cyclooxygenases, lipoxygenases and cytochrome P450 enzymes, and participate in many physiological and pathophysiological processes. For example, oxylipins regulate vascular tone, the onset of labor, pain, inflammation, fever and contribute to diseases such as asthma, cancer, arthritis, diabetes, obesity and neurodegenerative disorders. Understanding the mechanisms and cellular components involved in oxylipin biosynthesis is crucial for developing effective therapies that minimize complications and improve disease outcomes. Thus far, various animal models have increased our understanding of oxylipin biosynthesis and regulation in complex biological environments. These models have also facilitated the discovery of novel drug targets and the evaluation of drug safety and efficacy. However, each species used as a model system has its own advantages and limitations. Here we provide an overview of the most relevant and widely used models in lipid mediator research with a focus on 5-lipoxygenase and leukotriene pathway, emphasizing the significance of animal models in advancing our understanding of the complexities of leukotriene biology and its implications for human health.
{"title":"Animal models in leukotriene research: Current insights into complex pathways and therapeutic intervention","authors":"Tarvi Teder , Olof Rådmark , Jesper Z. Haeggström , Helike Lõhelaid","doi":"10.1016/j.pharmthera.2025.108944","DOIUrl":"10.1016/j.pharmthera.2025.108944","url":null,"abstract":"<div><div>Oxylipins are oxygenated bioactive lipid mediators formed from different polyunsaturated fatty acids through the bioactions of cyclooxygenases, lipoxygenases and cytochrome P450 enzymes, and participate in many physiological and pathophysiological processes. For example, oxylipins regulate vascular tone, the onset of labor, pain, inflammation, fever and contribute to diseases such as asthma, cancer, arthritis, diabetes, obesity and neurodegenerative disorders. Understanding the mechanisms and cellular components involved in oxylipin biosynthesis is crucial for developing effective therapies that minimize complications and improve disease outcomes. Thus far, various animal models have increased our understanding of oxylipin biosynthesis and regulation in complex biological environments. These models have also facilitated the discovery of novel drug targets and the evaluation of drug safety and efficacy. However, each species used as a model system has its own advantages and limitations. Here we provide an overview of the most relevant and widely used models in lipid mediator research with a focus on 5-lipoxygenase and leukotriene pathway, emphasizing the significance of animal models in advancing our understanding of the complexities of leukotriene biology and its implications for human health.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"276 ","pages":"Article 108944"},"PeriodicalIF":12.5,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-26DOI: 10.1016/j.pharmthera.2025.108941
Chen Huei Leo , Elizabeth A. Vecchio , Ting Fu , Xiangyan Yi , Cheng Peng , Peishen Zhao , Owen L. Woodman , Jonathan Baell , Rebecca H. Ritchie , Cheng Xue Qin
The formylpeptide receptor (FPR) family, particularly FPR2, has emerged as a master regulator of inflammation and its resolution. Given that both cardiovascular diseases and metabolic disorders are characterised by pro-inflammatory scenarios, often with resultant impairment of the healing response to (i.e. resolution of) inflammation, therapeutic targeting of the FPR family with judicious agonist selection provides new promise for tackling cardiometabolic disease. Here, we consider the pharmacology of this intriguing receptor family, the potential for novel biased signalling at its receptor subtypes and the current status of both endogenous and synthetic agonists (including peptides/proteins, small molecules and lipids) reported to be active at FPRs. A detailed review of the therapeutic potential of published FPR ligands involved in regulating and resolving inflammation in cardiometabolic disease is also provided. We anticipate that a broader understanding of, and greater appreciation for, the translational potential of pro-resolution FPR-based therapies may offer new effective means of targeting a range of cardiometabolic disorders and their resultant complications.
{"title":"Formylpeptide receptors: A novel target to treat cardiometabolic complications","authors":"Chen Huei Leo , Elizabeth A. Vecchio , Ting Fu , Xiangyan Yi , Cheng Peng , Peishen Zhao , Owen L. Woodman , Jonathan Baell , Rebecca H. Ritchie , Cheng Xue Qin","doi":"10.1016/j.pharmthera.2025.108941","DOIUrl":"10.1016/j.pharmthera.2025.108941","url":null,"abstract":"<div><div>The formylpeptide receptor (FPR) family, particularly FPR2, has emerged as a master regulator of inflammation and its resolution. Given that both cardiovascular diseases and metabolic disorders are characterised by pro-inflammatory scenarios, often with resultant impairment of the healing response to (i.e. resolution of) inflammation, therapeutic targeting of the FPR family with judicious agonist selection provides new promise for tackling cardiometabolic disease. Here, we consider the pharmacology of this intriguing receptor family, the potential for novel biased signalling at its receptor subtypes and the current status of both endogenous and synthetic agonists (including peptides/proteins, small molecules and lipids) reported to be active at FPRs. A detailed review of the therapeutic potential of published FPR ligands involved in regulating and resolving inflammation in cardiometabolic disease is also provided. We anticipate that a broader understanding of, and greater appreciation for, the translational potential of pro-resolution FPR-based therapies may offer new effective means of targeting a range of cardiometabolic disorders and their resultant complications.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"277 ","pages":"Article 108941"},"PeriodicalIF":12.5,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-08DOI: 10.1016/j.pharmthera.2025.108933
Lennard Spanehl , Thomas Grinda , Rishab Ramapriyan , Himanshu Soni , Sarah Blitz , Philip Heesen , Rohan Jha , Chibueze D. Nwagwu , Florian A. Gessler , Pablo Valdes , Sarah L. Sammons , Wenya Linda Bi , Gregory K. Friedman , Ayal A. Aizer , E. Antonio Chiocca , Nancy U. Lin , Joshua D. Bernstock
Leptomeningeal disease (LMD) associated with breast cancer (BC), characterized by the invasion of metastatic BC cells into the leptomeninges and cerebrospinal fluid, poses a significant clinical challenge. Current management strategies are not curative but rather aim to slow the rapid clinical decline associated with LMD, each with its own set of limitations. For instance, systemic chemotherapy faces delivery barriers while intrathecal administration directly targets the site of disease but struggles with uneven drug distribution, toxicity, and limited efficacy. Radiation therapy, including whole brain radiation, stereotactic radiosurgery, and proton craniospinal irradiation, offers palliative relief, though with varying levels of toxicity. The prognosis for patients with BC-associated LMD remains poor under existing treatment paradigms, highlighting an urgent need for innovative therapeutic strategies and delivery systems. Emerging approaches under investigation include advanced radiation techniques, targeted therapies, and novel immunotherapeutic modalities such as oncolytic viruses. Herein, we examine (1) contemporary treatment approaches for LMD in BC and (2) promising novel therapies that may reshape the management of this devastating condition.
{"title":"Treatment strategies for leptomeningeal disease in patients with breast cancer","authors":"Lennard Spanehl , Thomas Grinda , Rishab Ramapriyan , Himanshu Soni , Sarah Blitz , Philip Heesen , Rohan Jha , Chibueze D. Nwagwu , Florian A. Gessler , Pablo Valdes , Sarah L. Sammons , Wenya Linda Bi , Gregory K. Friedman , Ayal A. Aizer , E. Antonio Chiocca , Nancy U. Lin , Joshua D. Bernstock","doi":"10.1016/j.pharmthera.2025.108933","DOIUrl":"10.1016/j.pharmthera.2025.108933","url":null,"abstract":"<div><div>Leptomeningeal disease (LMD) associated with breast cancer (BC), characterized by the invasion of metastatic BC cells into the leptomeninges and cerebrospinal fluid, poses a significant clinical challenge. Current management strategies are not curative but rather aim to slow the rapid clinical decline associated with LMD, each with its own set of limitations. For instance, systemic chemotherapy faces delivery barriers while intrathecal administration directly targets the site of disease but struggles with uneven drug distribution, toxicity, and limited efficacy. Radiation therapy, including whole brain radiation, stereotactic radiosurgery, and proton craniospinal irradiation, offers palliative relief, though with varying levels of toxicity. The prognosis for patients with BC-associated LMD remains poor under existing treatment paradigms, highlighting an urgent need for innovative therapeutic strategies and delivery systems. Emerging approaches under investigation include advanced radiation techniques, targeted therapies, and novel immunotherapeutic modalities such as oncolytic viruses. Herein, we examine (1) contemporary treatment approaches for LMD in BC and (2) promising novel therapies that may reshape the management of this devastating condition.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"276 ","pages":"Article 108933"},"PeriodicalIF":12.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-08DOI: 10.1016/j.pharmthera.2025.108934
Runa Wang , Renshuai Zhang , Jun Zhou , Jie Ran
Angiogenesis, which entails the sprouting of new blood vessels from existing ones, is a critical process in normal development and tissue repair. However, when dysregulated, it contributes to a variety of diseases, including cancer, ischemic disorders, and chronic inflammation. Central to these processes are key factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Recent research has focused on therapeutic modulation of angiogenesis, employing both anti-angiogenic and pro-angiogenic strategies to regulate these pathways. Anti-angiogenic therapies primarily target the VEGF pathway to inhibit vessel formation, thereby reducing tumor vascularization in cancer and preventing abnormal blood vessel growth in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Conversely, pro-angiogenic therapies stimulate vessel growth to improve vascularization in conditions like coronary artery disease and Alzheimer's disease, enhancing tissue perfusion and promoting regeneration. In this review, we summarize current knowledge on targeted modulation of angiogenesis, detailing therapeutic strategies, the mechanisms that regulate vascular homeostasis, and their implications for disease management.
{"title":"Crosstalk between anti-angiogenic and pro-angiogenic pathways in disease: Mechanisms and therapeutic strategies","authors":"Runa Wang , Renshuai Zhang , Jun Zhou , Jie Ran","doi":"10.1016/j.pharmthera.2025.108934","DOIUrl":"10.1016/j.pharmthera.2025.108934","url":null,"abstract":"<div><div>Angiogenesis, which entails the sprouting of new blood vessels from existing ones, is a critical process in normal development and tissue repair. However, when dysregulated, it contributes to a variety of diseases, including cancer, ischemic disorders, and chronic inflammation. Central to these processes are key factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Recent research has focused on therapeutic modulation of angiogenesis, employing both anti-angiogenic and pro-angiogenic strategies to regulate these pathways. Anti-angiogenic therapies primarily target the VEGF pathway to inhibit vessel formation, thereby reducing tumor vascularization in cancer and preventing abnormal blood vessel growth in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Conversely, pro-angiogenic therapies stimulate vessel growth to improve vascularization in conditions like coronary artery disease and Alzheimer's disease, enhancing tissue perfusion and promoting regeneration. In this review, we summarize current knowledge on targeted modulation of angiogenesis, detailing therapeutic strategies, the mechanisms that regulate vascular homeostasis, and their implications for disease management.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"276 ","pages":"Article 108934"},"PeriodicalIF":12.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.pharmthera.2025.108932
Fengchao Lang, Chunzhang Yang
Glioma is a devastating disease associated with unfavorable clinical outcomes. Current standard treatments, including surgery, radiotherapy, and chemotherapy, are largely palliative and offer limited improvements in survival rates. Glioma is characterized by high proliferative capacity, which is primarily through exploiting the dysregulated cell cycle mechanisms for disease progression. Over the past few decades, targeting the glioma cell cycle—particularly key molecules involved in cell cycle checkpoints—has been a promising direction for future glioma therapeutics. In this review, we summarize the distinctive molecular patterns of cell cycle in glioma, and discuss emerging targeted therapies designed for glioma cell cycle regulators.
{"title":"Targeting cell cycle checkpoints for glioma therapy","authors":"Fengchao Lang, Chunzhang Yang","doi":"10.1016/j.pharmthera.2025.108932","DOIUrl":"10.1016/j.pharmthera.2025.108932","url":null,"abstract":"<div><div>Glioma is a devastating disease associated with unfavorable clinical outcomes. Current standard treatments, including surgery, radiotherapy, and chemotherapy, are largely palliative and offer limited improvements in survival rates. Glioma is characterized by high proliferative capacity, which is primarily through exploiting the dysregulated cell cycle mechanisms for disease progression. Over the past few decades, targeting the glioma cell cycle—particularly key molecules involved in cell cycle checkpoints—has been a promising direction for future glioma therapeutics. In this review, we summarize the distinctive molecular patterns of cell cycle in glioma, and discuss emerging targeted therapies designed for glioma cell cycle regulators.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108932"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-30DOI: 10.1016/j.pharmthera.2025.108931
George M. Turco , Sapna Oberoi , Brian Ladle , Raavi , Lars Wagner , Angela N. Koehler , Corinne M. Linardic
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The fusion-positive variant of rhabdomyosarcoma has the dubious distinction of being one of the most difficult to cure childhood cancers. Although the gene fusions PAX3::FOXO1 and PAX7::FOXO1 were discovered in the early 1990s, and since that time shown to be the molecular drivers of the disease, the best treatment to date still remains VAC (vincristine, actinomycin D, cyclophosphamide) combination therapy, first instituted as standard of care in the 1970s. Here we review the history, contemporary application, clinical evaluation, and future of fusion positive rhabdomyosarcoma systemic therapy. It is hoped that a better understanding of the underlying biology and the effective leverage of new strategies for targeting RNA, proteins, and the immune system will result in meaningful advances for treating this aggressive childhood cancer.
{"title":"Towards directed therapy for fusion-positive rhabdomyosarcoma","authors":"George M. Turco , Sapna Oberoi , Brian Ladle , Raavi , Lars Wagner , Angela N. Koehler , Corinne M. Linardic","doi":"10.1016/j.pharmthera.2025.108931","DOIUrl":"10.1016/j.pharmthera.2025.108931","url":null,"abstract":"<div><div>Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The fusion-positive variant of rhabdomyosarcoma has the dubious distinction of being one of the most difficult to cure childhood cancers. Although the gene fusions <em>PAX3::FOXO1</em> and <em>PAX7::FOXO1</em> were discovered in the early 1990s, and since that time shown to be the molecular drivers of the disease, the best treatment to date still remains VAC (vincristine, actinomycin D, cyclophosphamide) combination therapy, first instituted as standard of care in the 1970s. Here we review the history, contemporary application, clinical evaluation, and future of fusion positive rhabdomyosarcoma systemic therapy. It is hoped that a better understanding of the underlying biology and the effective leverage of new strategies for targeting RNA, proteins, and the immune system will result in meaningful advances for treating this aggressive childhood cancer.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"276 ","pages":"Article 108931"},"PeriodicalIF":12.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1016/j.pharmthera.2025.108930
Shuangshuang Wei , Ying Fu , Yuqing Zeng , Wenwen Wu , Juan Cai , Zheng Dong
Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid loss of renal function with high rates of morbidity and mortality. After AKI, the kidney may repair but the repair is often incomplete or maladaptive resulting in chronic pathologies for the development of chronic kidney disease (CKD). Emerging evidence highlights significant alterations in renal lipid profiles in both AKI and CKD models and human patients. The disturbances in lipid metabolism, characterized by lipid accumulation, lipid peroxidation, and subsequent development of a lipotoxic inflammatory milieu, are intricately linked to both the initiation of AKI and its transition or progression to CKD. Current research has focused on unraveling the changes in lipid metabolism and pinpoint the role of lipid dysregulation in AKI and AKI-CKD transition. In addition, pharmacological interventions targeting lipid metabolism have shown therapeutic promise in these disease models.
{"title":"Lipid metabolism in AKI and AKI-CKD transition: Dysregulation, lipotoxicity and therapeutic potential","authors":"Shuangshuang Wei , Ying Fu , Yuqing Zeng , Wenwen Wu , Juan Cai , Zheng Dong","doi":"10.1016/j.pharmthera.2025.108930","DOIUrl":"10.1016/j.pharmthera.2025.108930","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid loss of renal function with high rates of morbidity and mortality. After AKI, the kidney may repair but the repair is often incomplete or maladaptive resulting in chronic pathologies for the development of chronic kidney disease (CKD). Emerging evidence highlights significant alterations in renal lipid profiles in both AKI and CKD models and human patients. The disturbances in lipid metabolism, characterized by lipid accumulation, lipid peroxidation, and subsequent development of a lipotoxic inflammatory milieu, are intricately linked to both the initiation of AKI and its transition or progression to CKD. Current research has focused on unraveling the changes in lipid metabolism and pinpoint the role of lipid dysregulation in AKI and AKI-CKD transition. In addition, pharmacological interventions targeting lipid metabolism have shown therapeutic promise in these disease models.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108930"},"PeriodicalIF":12.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1016/j.pharmthera.2025.108929
Zachary McCalla, Xinwen Wang
Mass spectrometry-based absolute quantitative proteomics has emerged as a powerful method for accurately quantifying hepatic drug-metabolizing enzymes, which play a crucial role in drug disposition and therapeutic outcomes. Understanding the absolute drug-metabolizing enzyme protein concentrations and the associated interindividual variability in the liver, a primary organ for drug metabolism, is essential for developing predictive models for personalized pharmacotherapy. Over the past few decades, the rapid advancement of mass spectrometry-based proteomics has enabled the application of various techniques to study drug-metabolizing enzymes, significantly enhancing our understanding of their isoform composition in the liver. However, a focused review on mass spectrometry-based absolute protein quantification of human hepatic drug-metabolizing enzymes remains lacking. This review introduces commonly used strategies in mass spectrometry-based absolute protein quantification and summarizes the absolute quantities of Phase I and Phase II hepatic drug-metabolizing enzymes. It also updates the isoform compositions of cytochrome P450s and uridine diphosphate glucuronosyltransferases and explores factors contributing to variability in quantifications across studies. Additionally, we discuss the genetic and non-genetic regulations of hepatic enzyme protein expressions, as revealed by mass-spectrometry based-proteomics. Despite its potential for clinical applications, MS-based proteomics faces challenges, such as sensitivity limitation, significant inter-study varibility, cellular heterogeneity, and a lack of integration with other omics data. Future advancements in mass spectrometry-based quantitative proteomics, including single-cell proteomics, multi-omics integration, and artificial intelligence-driven data analysis, hold promise for better understanding of drug metabolizing enzymes, improving predictions of drug responses, and optimizing therapeutic outcomes for patients.
{"title":"Mass spectrometry-based absolute quantitative proteomics of drug-metabolizing enzymes in human liver","authors":"Zachary McCalla, Xinwen Wang","doi":"10.1016/j.pharmthera.2025.108929","DOIUrl":"10.1016/j.pharmthera.2025.108929","url":null,"abstract":"<div><div>Mass spectrometry-based absolute quantitative proteomics has emerged as a powerful method for accurately quantifying hepatic drug-metabolizing enzymes, which play a crucial role in drug disposition and therapeutic outcomes. Understanding the absolute drug-metabolizing enzyme protein concentrations and the associated interindividual variability in the liver, a primary organ for drug metabolism, is essential for developing predictive models for personalized pharmacotherapy. Over the past few decades, the rapid advancement of mass spectrometry-based proteomics has enabled the application of various techniques to study drug-metabolizing enzymes, significantly enhancing our understanding of their isoform composition in the liver. However, a focused review on mass spectrometry-based absolute protein quantification of human hepatic drug-metabolizing enzymes remains lacking. This review introduces commonly used strategies in mass spectrometry-based absolute protein quantification and summarizes the absolute quantities of Phase I and Phase II hepatic drug-metabolizing enzymes. It also updates the isoform compositions of cytochrome P450s and uridine diphosphate glucuronosyltransferases and explores factors contributing to variability in quantifications across studies. Additionally, we discuss the genetic and non-genetic regulations of hepatic enzyme protein expressions, as revealed by mass-spectrometry based-proteomics. Despite its potential for clinical applications, MS-based proteomics faces challenges, such as sensitivity limitation, significant inter-study varibility, cellular heterogeneity, and a lack of integration with other omics data. Future advancements in mass spectrometry-based quantitative proteomics, including single-cell proteomics, multi-omics integration, and artificial intelligence-driven data analysis, hold promise for better understanding of drug metabolizing enzymes, improving predictions of drug responses, and optimizing therapeutic outcomes for patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"275 ","pages":"Article 108929"},"PeriodicalIF":12.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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