Pharmacological research最新文献

{"title":"Alternative splicing: A key regulator in T cell response and cancer immunotherapy","authors":"Caiyu Yong ,&nbsp;Yexin Liang ,&nbsp;Minmin Wang ,&nbsp;Weiwei Jin ,&nbsp;Xuefei Fan ,&nbsp;Zhengwen Wang ,&nbsp;Kui Cao ,&nbsp;Tong Wu ,&nbsp;Qian Li ,&nbsp;Cunjie Chang","doi":"10.1016/j.phrs.2025.107713","DOIUrl":"10.1016/j.phrs.2025.107713","url":null,"abstract":"<div><div>Alternative splicing (AS), a key post-transcriptional regulatory mechanism, is frequently dysregulated in cancer, driving both tumor progression and immune modulation. Aberrant AS influences antigen presentation, T cell activation, immune checkpoint regulation, and cytokine signaling, contributing to immune evasion but also presenting unique therapeutic vulnerabilities. Targeting AS has emerged as a promising strategy in cancer immunotherapy. Splicing-derived neoantigens have been identified as potent inducers of CD8⁺ T cell responses, offering potential for personalized treatment. AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Furthermore, combining AS-targeting drugs with immune checkpoint inhibitors (ICIs) has demonstrated synergistic effects, improved response rates and overcoming resistance in preclinical models. Despite these advances, challenges remain in optimizing drug specificity and minimizing toxicity. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107713"},"PeriodicalIF":9.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DIORS: Enhancing drug-target interaction prediction via structure and signature integrated-driven approach and discovering potential targeted molecules","authors":"Yiran Tang ,&nbsp;Shengqiao Gao ,&nbsp;Dan Luo ,&nbsp;Xuyong Jiang ,&nbsp;Xueru Zhao ,&nbsp;Wanting Hu ,&nbsp;Yongxiang Zhang ,&nbsp;Zhiyong Xiao ,&nbsp;Lu Han ,&nbsp;Wenxia Zhou","doi":"10.1016/j.phrs.2025.107710","DOIUrl":"10.1016/j.phrs.2025.107710","url":null,"abstract":"<div><div>Drug-target interaction prediction is critical for drug development. Through the integration of structural and transcriptional signature information, molecules both binding to the target and producing therapeutic activities could be found out to improve targeted drug prediction. Therefore, the approaches that integrate the two types of data are worth exploring. Here, we present an integrated method named Data Integration Oriented Repurposing Strategy (DIORS) combining molecular docking and gene-signature matching to enhance the prediction of protein-targeted drugs. The StandardScaler algorithm was selected after evaluation of five algorithms and was used in DIORS. Surface Plasmon Resonance (SPR) was used to verify the molecular affinities and cell-based assays were used to verify the activities of DIORS predicted molecules. In Piezo1-targeted molecule prediction, among the top ten predicted molecules by DIORS, four of them, namely gefitinib, rifaximin, bosutinib and vandetanib, exhibited binding affinities. In the prediction of TLR4/MD2-targeted anti-inflammatory molecules, among the top ten predicted molecules, three of them, namely enoxolone, dabrafenib and ponatinib, exhibit both high binding affinities and anti-inflammatory activities. The results demonstrated that DIORS can serve as a better approach with high performance to predict and find new targeted drugs by combining structural and signature information.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107710"},"PeriodicalIF":9.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR1 inhibition sensitizes multiple myeloma cells to glucocorticoid therapy","authors":"Bert Luyckx ,&nbsp;Maaike Van Trimpont ,&nbsp;Fien Declerck ,&nbsp;Eleni Staessens ,&nbsp;Annick Verhee ,&nbsp;Sara T’Sas ,&nbsp;Sven Eyckerman ,&nbsp;Fritz Offner ,&nbsp;Pieter Van Vlierberghe ,&nbsp;Steven Goossens ,&nbsp;Dorien Clarisse ,&nbsp;Karolien De Bosscher","doi":"10.1016/j.phrs.2025.107709","DOIUrl":"10.1016/j.phrs.2025.107709","url":null,"abstract":"<div><div>Glucocorticoids (GC) are cornerstone drugs in the treatment of multiple myeloma (MM). Because MM cells exploit the bone marrow microenvironment to obtain growth and survival signals, resistance to glucocorticoid-induced apoptosis emerges, yet the underlying mechanisms remain poorly characterized. Here, we identify that the chemokine receptor CCR1, together with its main ligand CCL3, plays a pivotal role in reducing the glucocorticoid sensitivity of MM cells. We show that blocking CCR1 signaling with the antagonist BX471 enhances the anti-MM effects of the glucocorticoid dexamethasone in MM cell lines, primary patient material and a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. Our findings suggest that CCR1 may play a role in glucocorticoid resistance, as the GC-induced downregulation of CCR1 mRNA and protein is blunted in a GC-resistance onset model. Moreover, we demonstrate that inhibiting CCR1 partially reverses this resistance, providing a promising strategy for resensitizing MM cells to GC treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107709"},"PeriodicalIF":9.1,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease” [Pharmacol. Res. 18 (2025), 212:107617. doi: 10.1016/j.phrs.2025.107617]","authors":"Lulu Zhang ,&nbsp;Yi Zheng ,&nbsp;Mingyan Shao ,&nbsp;Aiping Chen ,&nbsp;Meiyi Liu ,&nbsp;Wenlong Sun ,&nbsp;Tianxing Li ,&nbsp;Yini Fang ,&nbsp;Yang Dong ,&nbsp;Shipeng Zhao ,&nbsp;Hui Luo ,&nbsp;Juan Feng ,&nbsp;Qi Wang ,&nbsp;Lingru Li ,&nbsp;Yanfei Zheng","doi":"10.1016/j.phrs.2025.107689","DOIUrl":"10.1016/j.phrs.2025.107689","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107689"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693092","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}

{"title":"Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement","authors":"Mengdi Zhang ,&nbsp;Jinliang Ji ,&nbsp;Yuanyuan Lei ,&nbsp;Fujian Qin ,&nbsp;Yitong Tao ,&nbsp;Ning Li ,&nbsp;Jinlei Bian ,&nbsp;Zhiyu Li ,&nbsp;Maode Lai ,&nbsp;Zhixia Qiu","doi":"10.1016/j.phrs.2025.107706","DOIUrl":"10.1016/j.phrs.2025.107706","url":null,"abstract":"<div><div>Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction—a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107706"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBX4 regulation of senescence and associated diseases: Molecular pathways and mechanisms","authors":"Qianxing Hu ,&nbsp;Linming Su ,&nbsp;Wanli Zhao ,&nbsp;Yinuo Jin ,&nbsp;Liang Jin ,&nbsp;Yue Yang ,&nbsp;Fangfang Zhang","doi":"10.1016/j.phrs.2025.107705","DOIUrl":"10.1016/j.phrs.2025.107705","url":null,"abstract":"<div><div>Polycomb repressive complex 1 (PRC1) is a multisubunit, evolutionarily conserved epigenetic regulator critical to numerous biological processes. Being a core component of the canonical PRC1 subunit within the Polycomb group protein complex, Chromobox4 (CBX4), a SUMO E3 ligase, can bind to H3K27me3 and recruit PRC1. This ligase regulates the SUMOylation of various proteins and permits their post-translational modification under different physiological conditions. CBX4 has been reported to regulate the development of senescence and various diseases <em>in vivo</em>. This review delves into the physiological functions and action mechanisms of CBX4 across different tissues and cells, particularly focusing on its primarily roles in migration, cellular senescence, metabolic dysregulation, inflammation development, and tumor proliferation. Targeting CBX4 offers a therapeutic potential for delaying cell senescence and suppressing tumor growth.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107705"},"PeriodicalIF":9.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to letter to the editor: Letter by Chen et al. regarding article, “Assessment of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer's disease: A population-based study”","authors":"Mar Garcia – Zamora,&nbsp;Gemma García – Lluch,&nbsp;Lucrecia Moreno,&nbsp;Consuelo Cháfer – Pericás,&nbsp;Juan Pardo","doi":"10.1016/j.phrs.2025.107701","DOIUrl":"10.1016/j.phrs.2025.107701","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107701"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674501","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}

{"title":"Cleavage of the TrkB-FL receptor during epileptogenesis: insights from a kainic acid-induced model of epilepsy and human samples","authors":"Leonor Ribeiro-Rodrigues ,&nbsp;João Fonseca-Gomes ,&nbsp;Sara L. Paulo ,&nbsp;Ricardo Viais ,&nbsp;Filipa F. Ribeiro ,&nbsp;Catarina Miranda-Lourenço ,&nbsp;Francisco M. Mouro ,&nbsp;Rita F. Belo ,&nbsp;Catarina B. Ferreira ,&nbsp;Sara R. Tanqueiro ,&nbsp;Mafalda Ferreira-Manso ,&nbsp;Juzoh Umemori ,&nbsp;Eero Castrén ,&nbsp;Vítor H. Paiva ,&nbsp;Ana M. Sebastião ,&nbsp;Eleonora Aronica ,&nbsp;Alexandre Rainha Campos ,&nbsp;Carla Bentes ,&nbsp;Sara Xapelli ,&nbsp;Maria José Diógenes","doi":"10.1016/j.phrs.2025.107707","DOIUrl":"10.1016/j.phrs.2025.107707","url":null,"abstract":"<div><div>Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity. In epilepsy, BDNF exhibits a dual role, exerting both antiepileptic and pro-epileptic effects. The cleavage of its main receptor, full-length tropomyosin-related kinase B (TrkB-FL), was suggested to occur in status epilepticus (SE) in vitro. Moreover, under excitotoxic conditions, TrkB-FL was found to be cleaved, resulting in the formation of a new intracellular fragment, TrkB-ICD. Thus, we hypothesized that TrkB-FL cleavage and TrkB-ICD formation could represent an uncovered mechanism in epilepsy. We used a rat model of mesial temporal lobe epilepsy (mTLE) induced by kainic acid (KA) to investigate TrkB-FL cleavage and TrkB-ICD formation during SE (∼3 h after KA) and established epilepsy (EE) (4–5 weeks after KA). Animals treated with 10 mg/kg of KA exhibited TrkB-FL cleavage during SE, with hippocampal levels of TrkB-FL and TrkB-ICD correlating with seizure severity. Notably, TrkB-FL cleavage and TrkB-ICD formation were also detected in animals with EE, which exhibited spontaneous recurrent convulsive seizures, neuronal death, mossy fiber sprouting, and long-term memory impairment. Importantly, hippocampal samples from patients with refractory epilepsy also showed TrkB-FL cleavage with increased TrkB-ICD levels. Additionally, lentiviral-mediated overexpression of TrkB-ICD in the hippocampus of healthy mice and rats resulted in long-term memory impairment. Our findings suggest that TrkB-FL cleavage and the subsequent TrkB-ICD production occur throughout epileptogenesis, with the extent of cleavage correlating positively with seizure occurrence. Moreover, we found that TrkB-ICD overexpression impairs memory. This work uncovers a novel mechanism in epileptogenesis that could serve as a potential therapeutic target in mTLE, with implications for preserving cognitive function.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107707"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on “Assessment of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer’s disease: A population-based study”","authors":"Feng Chen,&nbsp;Zhong Wang","doi":"10.1016/j.phrs.2025.107702","DOIUrl":"10.1016/j.phrs.2025.107702","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107702"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674498","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}

{"title":"CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent in hepatocellular carcinoma","authors":"Zuhui Liang ,&nbsp;Yingyi Ye ,&nbsp;Zhihong Deng ,&nbsp;Huan Lan ,&nbsp;Caihong Liu ,&nbsp;Yuanhang Xu ,&nbsp;Minqi Fan ,&nbsp;Zhongqiu Liu ,&nbsp;Peng Wu ,&nbsp;Lin An ,&nbsp;Caiyan Wang","doi":"10.1016/j.phrs.2025.107698","DOIUrl":"10.1016/j.phrs.2025.107698","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) was associated with high morbidity and mortality, representing a significant health challenge. Chondroitin sulfate (CS), a glycosaminoglycan composed of glucuronic acid and N-acetylgalactosamine, is implicated in HCC progression through its role in cancer cell migration and proliferation as well as interactions with cell surface receptors integrin β-1 and CD44. Chondroitin polymerization factor 2 (CHPF2), the key to CS synthesis, has an undefined role in HCC. Our study aims to demonstrate that decreasing CHPF2 enzyme activity can inhibit the migration and proliferation of HCC cells. Bioinformatics analysis and in vitro experiments on clinical HCC samples confirmed the knockdown of CHPF2 inhibited HCC cell proliferation and migration. We further explored <em>Rabdosia rubescens</em>, a plant used in cancer therapy, for its potential to modulate CHPF2. Structural biology and ligand fishing identified ponicidin, a compound that significantly suppresses HCC cell growth and migration in both in vitro and in vivo models. These findings propose CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent for HCC management.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107698"},"PeriodicalIF":9.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}