Pub Date : 2025-12-11DOI: 10.1016/j.phrs.2025.108064
Chunsik Lee , Myung-Jin Kim , Eunyoung Jung , Jianing Zhang , Vivek Hamse Kameshwar , Nayoung Oh , Anil Kumar , Han-Woong Lee , Xuri Li , Yonghwan Kim
Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.
{"title":"VEGF-B: A multifaceted modulator with emerging therapeutic applications","authors":"Chunsik Lee , Myung-Jin Kim , Eunyoung Jung , Jianing Zhang , Vivek Hamse Kameshwar , Nayoung Oh , Anil Kumar , Han-Woong Lee , Xuri Li , Yonghwan Kim","doi":"10.1016/j.phrs.2025.108064","DOIUrl":"10.1016/j.phrs.2025.108064","url":null,"abstract":"<div><div>Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108064"},"PeriodicalIF":10.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.phrs.2025.108063
Mirko G. Liturri, A. Bergna, A. Lai, C. Della Ventura, A. Gabrieli, I. Seravalli, S. Ciofi-Baffoni, E. Lenci, A. Trabocchi, S. Rusconi
{"title":"Evaluation of in vitro antiviral activity against different SARS-CoV-2 variants of a protease PROTAC degrader","authors":"Mirko G. Liturri, A. Bergna, A. Lai, C. Della Ventura, A. Gabrieli, I. Seravalli, S. Ciofi-Baffoni, E. Lenci, A. Trabocchi, S. Rusconi","doi":"10.1016/j.phrs.2025.108063","DOIUrl":"10.1016/j.phrs.2025.108063","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108063"},"PeriodicalIF":10.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1016/j.phrs.2025.108062
Rigen Mo , Sarah Lucas , Xiao-Jiang Feng , Adrian Hackett , Ed Skucas , Kevin G. Liu , Ji-In Kim , Pegah Kolahi , Jack Gaffney , Jillian J. Spinney , Rachel S. Knipe , Jeegar P. Patel , M. Kathryn Steiner , Serra Elliott , William Marshall , James Hui , Shawn N. Grant , Masha V. Poyurovsky
Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage in vivo. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure–lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.
{"title":"Pharmacological profile and therapeutic evaluation of ROC-101, a potent and selective ROCK inhibitor, in arterial hypertension and pulmonary fibrosis","authors":"Rigen Mo , Sarah Lucas , Xiao-Jiang Feng , Adrian Hackett , Ed Skucas , Kevin G. Liu , Ji-In Kim , Pegah Kolahi , Jack Gaffney , Jillian J. Spinney , Rachel S. Knipe , Jeegar P. Patel , M. Kathryn Steiner , Serra Elliott , William Marshall , James Hui , Shawn N. Grant , Masha V. Poyurovsky","doi":"10.1016/j.phrs.2025.108062","DOIUrl":"10.1016/j.phrs.2025.108062","url":null,"abstract":"<div><div>Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage <em>in vivo</em>. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure–lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming <em>in vivo</em> target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These <em>in vivo</em> and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108062"},"PeriodicalIF":10.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.phrs.2025.108053
Jing Wang , Chenyu Lin , Pengbo Zhang , Xixi Huang , Wei Zhou , Mufan Wu , Jiaming Wang , Fenyong Sun , Bingdi Chen
Platelets play a critical role in tumor progression and metastasis, yet the mechanisms by which they influence cancer cell behavior remain unclear. In this study, we investigated the interaction between platelets and colorectal cancer (CRC) cells and identified CAP-1 as a key mediator of platelet-induced tumor metastasis. Transcriptomic analyses showed that tumor-educated platelets induced significant gene expression changes in CRC cells, particularly involving pathways related to adhesion and migration. By intersecting upregulated genes in both tumor cells and patient-derived platelets, CAP-1 was identified and functionally validated as a critical gene using in vitro knockdown and in vivo metastasis models. CAP-1 depletion significantly impaired tumor cell migration, adhesion, cytoskeletal organization, and lung metastasis in mice without affecting cell proliferation or viability. A shape-based virtual screening strategy identified small-molecule CAP-1 inhibitors, among which compound CAPib-13 demonstrated strong binding affinity (KD = 2.57 µM), effectively inhibited tumor metastasis in vivo, and showed no significant toxicity. These findings uncover a novel role for CAP-1 in mediating platelet-cancer cell interactions and suggest that CAP-1 inhibition represents a promising therapeutic strategy for metastatic colorectal cancer.
{"title":"Targeting platelet-mediated CAP-1 upregulation in colorectal cancer: Mechanisms and small-molecule inhibitor development","authors":"Jing Wang , Chenyu Lin , Pengbo Zhang , Xixi Huang , Wei Zhou , Mufan Wu , Jiaming Wang , Fenyong Sun , Bingdi Chen","doi":"10.1016/j.phrs.2025.108053","DOIUrl":"10.1016/j.phrs.2025.108053","url":null,"abstract":"<div><div>Platelets play a critical role in tumor progression and metastasis, yet the mechanisms by which they influence cancer cell behavior remain unclear. In this study, we investigated the interaction between platelets and colorectal cancer (CRC) cells and identified CAP-1 as a key mediator of platelet-induced tumor metastasis. Transcriptomic analyses showed that tumor-educated platelets induced significant gene expression changes in CRC cells, particularly involving pathways related to adhesion and migration. By intersecting upregulated genes in both tumor cells and patient-derived platelets, CAP-1 was identified and functionally validated as a critical gene using <em>in vitro</em> knockdown and <em>in vivo</em> metastasis models. CAP-1 depletion significantly impaired tumor cell migration, adhesion, cytoskeletal organization, and lung metastasis in mice without affecting cell proliferation or viability. A shape-based virtual screening strategy identified small-molecule CAP-1 inhibitors, among which compound CAPib-13 demonstrated strong binding affinity (K<sub>D</sub> = 2.57 µM), effectively inhibited tumor metastasis <em>in vivo</em>, and showed no significant toxicity. These findings uncover a novel role for CAP-1 in mediating platelet-cancer cell interactions and suggest that CAP-1 inhibition represents a promising therapeutic strategy for metastatic colorectal cancer.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108053"},"PeriodicalIF":10.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108049
Guoming Chen , Qianhua He , Qili Xiao , Jiaqi Ai , Zhengya Qin , Zilan Zhong , Jiayi Zou , Bonan Chen , Cheng Zhang , Yibin Feng
As a major obstacle in cancer treatment, drug resistance is increasingly recognized that non-coding RNA (ncRNA) plays an important role in regulating cell plasticity. This review comprehensively explores how ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, drive drug resistance by altering identity plasticity (epithelial-mesenchymal transition and stemness), state plasticity (cell fate selection and metabolic reprogramming), and communication plasticity in the tumor microenvironment. Due to the complexity of the ncRNA network, Chinese medicines (CMs) with multi-target properties have become a potential modulator. Preclinical evidence suggests that certain CMs and their bioactive compounds have been shown to inhibit therapeutic resistance by regulating various ncRNAs. For instance, curcumin upregulates miR-206 to inhibit the JAK/STAT3 pathway in colorectal cancer, while in gastric cancer, β-elemene inhibits miR-1323 to prevent EGFR-driven epithelial-mesenchymal transition. However, current clinical research is still in the preliminary exploration stage and lacks high-quality, large-scale, prospective randomized controlled trials.
Conclusions
From a mechanistic perspective, CMs targeting ncRNAs present a potential multi-target strategy against cancer drug resistance, but their clinical translation remains largely theoretical. Bridging this gap requires future research to prioritize in-depth mechanism studies, advanced delivery systems, and rigorous clinical validation related to ncRNA biomarkers.
{"title":"The role of Chinese medicines in targeting non-coding RNAs to overcome cancer drug resistance: Mechanisms and clinical translation challenges","authors":"Guoming Chen , Qianhua He , Qili Xiao , Jiaqi Ai , Zhengya Qin , Zilan Zhong , Jiayi Zou , Bonan Chen , Cheng Zhang , Yibin Feng","doi":"10.1016/j.phrs.2025.108049","DOIUrl":"10.1016/j.phrs.2025.108049","url":null,"abstract":"<div><div>As a major obstacle in cancer treatment, drug resistance is increasingly recognized that non-coding RNA (ncRNA) plays an important role in regulating cell plasticity. This review comprehensively explores how ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, drive drug resistance by altering identity plasticity (epithelial-mesenchymal transition and stemness), state plasticity (cell fate selection and metabolic reprogramming), and communication plasticity in the tumor microenvironment. Due to the complexity of the ncRNA network, Chinese medicines (CMs) with multi-target properties have become a potential modulator. Preclinical evidence suggests that certain CMs and their bioactive compounds have been shown to inhibit therapeutic resistance by regulating various ncRNAs. For instance, curcumin upregulates miR-206 to inhibit the JAK/STAT3 pathway in colorectal cancer, while in gastric cancer, β-elemene inhibits miR-1323 to prevent EGFR-driven epithelial-mesenchymal transition. However, current clinical research is still in the preliminary exploration stage and lacks high-quality, large-scale, prospective randomized controlled trials.</div></div><div><h3>Conclusions</h3><div>From a mechanistic perspective, CMs targeting ncRNAs present a potential multi-target strategy against cancer drug resistance, but their clinical translation remains largely theoretical. Bridging this gap requires future research to prioritize in-depth mechanism studies, advanced delivery systems, and rigorous clinical validation related to ncRNA biomarkers.</div></div><div><h3>Chemical Compounds in this article</h3><div>Curcumin; Berberine; β-Elemene; Astragaloside IV; Icariin; Matrine; Toosendanin; Artesunate; Resveratrol; Cantharidin</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108049"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108051
Sophie Post , Lena Rueschpler , Sebastian Schloer
Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.
{"title":"Endolysosomes as a sorting hub for emerging viruses: Gatekeepers of cellular defense, viral fate and promising therapeutic target","authors":"Sophie Post , Lena Rueschpler , Sebastian Schloer","doi":"10.1016/j.phrs.2025.108051","DOIUrl":"10.1016/j.phrs.2025.108051","url":null,"abstract":"<div><div>Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108051"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108058
Robert Roskoski Jr.
The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, inter alia, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including BRCA1/2 mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski’s rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.
{"title":"Poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of cancer","authors":"Robert Roskoski Jr.","doi":"10.1016/j.phrs.2025.108058","DOIUrl":"10.1016/j.phrs.2025.108058","url":null,"abstract":"<div><div>The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, <em>inter alia</em>, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including <em>BRCA1/2</em> mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski’s rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108058"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108014
Guido Grassi
{"title":"The saga of the guidelines on hypertension: Focus on the 2025 ACC/AHA document","authors":"Guido Grassi","doi":"10.1016/j.phrs.2025.108014","DOIUrl":"10.1016/j.phrs.2025.108014","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108014"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108061
Bingchen Pan , Tan Li , Na Deng , Xin Zhang , Yangjie Peng , Yanke Li , Jingjing Jing , Liping Sun
Solute carrier (SLC) transporters exert a crucial effect on metalloptosis in tumors via governing the translocation of ions and amino acids across cellular and organelle membranes. Disruptions in metal ion homeostasis mediated by SLC transporters, along with the subsequent induction of metalloptosis, are pivotal factors in tumor initiation and progression. However, the precise biological roles and clinical implications of SLC transporters in cancer remain incompletely interpreted. This review systematically summarizes the structural and functional features of SLC transporters in mediating metalloptosis and underscores their significant roles in cancer biology. We further delineate the regulatory mechanisms of SLC transporters in metal ion flux and amino acid metabolism, emphasizing their dynamic interplay in modulating metalloptosis during tumorigenesis. Furthermore, we provide a detailed overview of the complex crosstalk among SLC transporters, metal ions, and metalloptosis pathways, and highlight the role of SLC transporters in cancer, paving novel avenues for innovative anticancer strategies.
{"title":"SLC transporters as metalloptotic gatekeepers in tumorigenesis: From molecular mechanisms to clinical potential","authors":"Bingchen Pan , Tan Li , Na Deng , Xin Zhang , Yangjie Peng , Yanke Li , Jingjing Jing , Liping Sun","doi":"10.1016/j.phrs.2025.108061","DOIUrl":"10.1016/j.phrs.2025.108061","url":null,"abstract":"<div><div>Solute carrier (SLC) transporters exert a crucial effect on metalloptosis in tumors via governing the translocation of ions and amino acids across cellular and organelle membranes. Disruptions in metal ion homeostasis mediated by SLC transporters, along with the subsequent induction of metalloptosis, are pivotal factors in tumor initiation and progression. However, the precise biological roles and clinical implications of SLC transporters in cancer remain incompletely interpreted. This review systematically summarizes the structural and functional features of SLC transporters in mediating metalloptosis and underscores their significant roles in cancer biology. We further delineate the regulatory mechanisms of SLC transporters in metal ion flux and amino acid metabolism, emphasizing their dynamic interplay in modulating metalloptosis during tumorigenesis. Furthermore, we provide a detailed overview of the complex crosstalk among SLC transporters, metal ions, and metalloptosis pathways, and highlight the role of SLC transporters in cancer, paving novel avenues for innovative anticancer strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108061"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108046
Bing Shu , Xisha Chen , Zhonghao Liu , Huifang Tang , Bo Yang , Chengxiao Fu
SGLT2 inhibitors, initially developed for type 2 diabetes management, have primarily demonstrated pleiotropic benefits in cardiovascular, renal, pulmonary, digestive and endocrine/metabolic, et al. Emerging evidence highlights their immunomodulatory effects on macrophages, key players in disease pathogenesis. This review summarizes the mechanisms by which dapagliflozin, empagliflozin, and canagliflozin regulate macrophage polarization, metabolic reprogramming, and inflammatory responses. These drugs suppress pro-inflammatory M1 macrophage activation, promote anti-inflammatory M2 phenotypes, and reduce the release of cytokines (e.g., IL-1β, IL-6,TNF-α) through pathways such as NF-κB, AMPK/mTOR, and JAK/STAT. In cardiovascular diseases, they attenuate atherosclerosis (AS) and myocardial fibrosis by limiting macrophage infiltration and foam cell formation. Renal protection is mediated via reduced macrophage-driven inflammation and fibrosis in diabetic and non-diabetic kidney injury. Additionally, their anti-inflammatory effects extend toothers like non-alcoholic fatty liver disease and inflammatory bowel disease. Collectively, SGLT2 inhibitors exhibit multi-organ protective potential through macrophage modulation, positioning them as promising immunomodulatory agents beyond glucose-lowering therapy.
{"title":"Pleiotropic effects of SGLT2 inhibitors: A focus on macrophage-mediated action","authors":"Bing Shu , Xisha Chen , Zhonghao Liu , Huifang Tang , Bo Yang , Chengxiao Fu","doi":"10.1016/j.phrs.2025.108046","DOIUrl":"10.1016/j.phrs.2025.108046","url":null,"abstract":"<div><div>SGLT2 inhibitors, initially developed for type 2 diabetes management, have primarily demonstrated pleiotropic benefits in cardiovascular, renal, pulmonary, digestive and endocrine/metabolic, et al. Emerging evidence highlights their immunomodulatory effects on macrophages, key players in disease pathogenesis. This review summarizes the mechanisms by which dapagliflozin, empagliflozin, and canagliflozin regulate macrophage polarization, metabolic reprogramming, and inflammatory responses. These drugs suppress pro-inflammatory M1 macrophage activation, promote anti-inflammatory M2 phenotypes, and reduce the release of cytokines (e.g., IL-1β, IL-6,TNF-α) through pathways such as NF-κB, AMPK/mTOR, and JAK/STAT. In cardiovascular diseases, they attenuate atherosclerosis (AS) and myocardial fibrosis by limiting macrophage infiltration and foam cell formation. Renal protection is mediated via reduced macrophage-driven inflammation and fibrosis in diabetic and non-diabetic kidney injury. Additionally, their anti-inflammatory effects extend toothers like non-alcoholic fatty liver disease and inflammatory bowel disease. Collectively, SGLT2 inhibitors exhibit multi-organ protective potential through macrophage modulation, positioning them as promising immunomodulatory agents beyond glucose-lowering therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108046"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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