Pharmacological research最新文献

{"title":"FASN targeting by G28UCM impairs mitochondrial fatty acid synthesis and reveals a FASN–SDHB synthetic interaction","authors":"Nastasia Wilfinger-Lutz ,&nbsp;Kristina M. Kuehrer ,&nbsp;Maria J. Bueno ,&nbsp;Michaela Schwaiger-Haber ,&nbsp;Wang Wen Ann ,&nbsp;Katrin Krejci ,&nbsp;Ronald Mekis ,&nbsp;Nicolle Gobbo Oliveira Erünlü ,&nbsp;Anne Miller ,&nbsp;Alexandra Junza ,&nbsp;Siegfried Reipert ,&nbsp;Michael Bergmann ,&nbsp;Oscar Yanes ,&nbsp;Arvand Haschemi ,&nbsp;Gunda Koellensperger ,&nbsp;Miguel Quintela-Fandino ,&nbsp;Karin Nowikovsky","doi":"10.1016/j.phrs.2026.108087","DOIUrl":"10.1016/j.phrs.2026.108087","url":null,"abstract":"<div><div>Metabolic reprogramming in cancer relies on lipid synthesis and mitochondrial function, yet how these processes, other than citrate flux and β-oxidation, intersect remains unclear. While inhibitors of lipogenic pathways have been developed as potential therapeutic agents in cancer therapy, their impact on oxidative metabolism is underexplored. Here, we identify the fatty acid synthase (FASN) inhibitor G28UCM as a compound that additionally destabilizes mitochondrial fatty acid synthase (mtFAS) and succinate dehydrogenase subunit B (SDHB), thereby targeting cytosolic and mitochondrial metabolism. Unexpectedly, the decreased abundance of SDHB was linked to disruption of mtFAS, most notably downregulation of Lipoyl Synthase (LIAS). G28UCM induced profound metabolic stress, including pseudohypoxia, oxidative stress, endoplasmic reticulum stress, and ferroptosis. In contrast, genetic depletion of FASN failed to reproduce these effects. In addition to investigating the mechanism of action of G28UCM, our study revealed a genetic interaction between FASN and SDHB, establishing that their dual but not single loss of function is sufficient to impair tumor growth. The synthetic interaction was conserved across prostate cancer, neuroendocrine tumors, and renal carcinoma cell models, including patient-derived cells, and combined inhibition of FASN and SDH markedly suppressed tumor progression in a breast cancer mouse model. Our findings point to new therapeutic opportunities for FASN inhibition beyond tumor initiation, with particular relevance to cancers associated with malignant SDHB mutations.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108087"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952770","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":"The addicted brain: How processed foods hijack reward pathways","authors":"Kaylee Hough ,&nbsp;Marzia Friuli ,&nbsp;Nicole M. Avena ,&nbsp;Adele Romano","doi":"10.1016/j.phrs.2026.108097","DOIUrl":"10.1016/j.phrs.2026.108097","url":null,"abstract":"<div><div>The concept of addiction, traditionally confined to substances such as drugs and alcohol, has expanded to encompass behavioral patterns such as compulsive eating. Emerging evidence suggests that ultra-processed foods (UPFs), particularly those high in refined sugars and saturated fats, may elicit neurobiological responses akin to those observed in substance use disorders. This review explores the hypothesis that food addiction shares common clinical and neurochemical mechanisms with traditional forms of addiction, drawing from DSM-5 diagnostic criteria and recent findings in neuropharmacology. Animal and human studies have demonstrated that excessive consumption of palatable foods can induce behaviors characteristic of addiction—bingeing, craving, tolerance, and withdrawal—accompanied by significant dopaminergic alterations within the mesolimbic reward circuitry. Neuroimaging and molecular studies further reveal that chronic overconsumption of UPFs alters dopaminergic tone, disrupts prefrontal control, and activates stress pathways, thereby reinforcing compulsive intake. The Yale Food Addiction Scale (YFAS) and its pediatric adaptations provide structured tools for identifying food addiction phenotypes in clinical and research settings. Moreover, parallels between binge eating disorder and substance dependence highlight overlapping neurobehavioral mechanisms. As the obesity epidemic intensifies, particularly among populations with limited access to nutritious foods, understanding the pharmacological underpinnings of food addiction becomes critical. This review underscores the need to reframe UPFs as potentially addictive agents and calls for integrative therapeutic strategies and policy-driven reforms aimed at mitigating their impact on public health.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108097"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959931","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":"A Mangifera indica L. extract functions as a broad TLR2/4/6 signalling rheostat to attenuate MyD88/NF-κB-driven inflammation and macrophage polarization","authors":"Anna Schettino ,&nbsp;Anella Saviano ,&nbsp;Noemi Marigliano ,&nbsp;Martina Smimmo ,&nbsp;Erika Esposito ,&nbsp;Jenefa Begum ,&nbsp;Areeba Fatima ,&nbsp;Alyssa M. Urbanowski ,&nbsp;Christopher Mahony ,&nbsp;Amnah M. Khormi ,&nbsp;Adel Abo Mansour ,&nbsp;Tariq H. Iqbal ,&nbsp;Helen M. McGettrick ,&nbsp;Asif Jilani Iqbal ,&nbsp;Francesco Maione","doi":"10.1016/j.phrs.2026.108099","DOIUrl":"10.1016/j.phrs.2026.108099","url":null,"abstract":"<div><div>Current therapies for immune-mediated diseases often lack precision, causing broad immunosuppression. While <em>Mangifera indica</em> L. extract (here referred to as MIE) shows promise in resolving pain and modulating adaptive immunity, its direct impact on monocyte recruitment and macrophage polarization, remains elusive. Using a reverse translational approach, we examined the effects of MIE on primary human monocytes and macrophages from healthy donors and inflammatory bowel disease (IBD) patients. We assessed its ability to inhibit monocyte transmigration across TNF-α-activated endothelial monolayers and to modulate macrophage polarization along the M1/M2 phenotypes. Transcriptomic profiling via RNA-seq revealed several MIE-responsive pathways in human macrophages, which were subsequently validated functionally using murine peritoneal macrophages stimulated with a panel of distinct toll-like receptors (TLRs) agonists. MIE markedly impaired monocyte adhesion and transmigration across activated endothelium. In human macrophages, it selectively attenuated the pro-inflammatory M1 phenotype, robustly suppressing TNF-α secretion from both healthy donors and IBD patients, while exerting minimal effects on the M2 profile. Transcriptomic analysis revealed that MIE disrupts key inflammatory signalling networks, notably those governed by NF-κB and TLRs. Mechanistically, MIE did not exert broad TLR inhibition but instead acted as a precise immunological rheostat, dampening responses to murine TLR2, TLR4, and TLR6 agonists. TLR4-targeted modulation was mediated via downregulation of MyD88 and NF-κB expression, culminating in reduced pro-inflammatory cytokine production. We delineate a novel mechanism for MIE as a selective rheostat of the TLR2/4/6 axis for restoring innate immune homeostasis in inflammatory-based diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108099"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990281","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":"Questions and comments on “ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation,” published in Pharmacological Research (2023)","authors":"Bing Bai,&nbsp;Wenming Bao,&nbsp;Ling Wang,&nbsp;Ningling Kang","doi":"10.1016/j.phrs.2026.108101","DOIUrl":"10.1016/j.phrs.2026.108101","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108101"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003605","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":"Benefits and risks of herbal medicine use during pregnancy on offspring outcomes: A systematic review and meta-analysis of randomized controlled trials and observational studies","authors":"Chen Chen ,&nbsp;Yuezhen Li ,&nbsp;Wenling Wang ,&nbsp;Chunrong Liu ,&nbsp;Qiumei Luo ,&nbsp;Yan Ren ,&nbsp;Yiquan Xiong ,&nbsp;Xin Sun ,&nbsp;Jing Tan","doi":"10.1016/j.phrs.2026.108092","DOIUrl":"10.1016/j.phrs.2026.108092","url":null,"abstract":"<div><h3>Purpose</h3><div>Herbal medicines are widely used during pregnancy, yet their potential effects on offspring remain uncertain. This systematic review aimed to comprehensively evaluate both the potential benefits and risks of prenatal herbal medicine use on offspring outcomes by synthesizing evidence from randomized controlled trials (RCTs) and observational studies.</div></div><div><h3>Methods</h3><div>We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to November 9, 2024. Eligible studies reported maternal use of herbal medicines during pregnancy and assessed offspring-related outcomes.</div></div><div><h3>Results</h3><div>A total of 111 studies met the inclusion criteria, comprising 39 RCTs, 36 cohort studies, 18 case–control studies, and 18 cross-sectional surveys. In RCTs, prenatal use of certain herbal medicines was associated the live birth rate (RR=1.14, 95 % CI: 1.05–1.24) and a lower risk of birth defects (RR=0.46, 95 % CI: 0.22–0.94), primarily among women undergoing assisted reproduction; reductions in miscarriage were observed among those with threatened or recurrent miscarriage. At the overall level, observational studies adjusted for confounding did not show significant associations between prenatal herbal medicine use and major adverse offspring outcomes (including birth defects, miscarriage, stillbirth, or preterm birth). Exploratory analyses of individual herbal products suggested that some specific herbs—such as almond oil and <em>Glycyrrhiza</em> (with preterm birth), betel quid (with low birth weight), An-Tai-Yin (with musculoskeletal malformations), khat (with nervous system malformations), and <em>Coptidis Rhizoma</em> (with nervous system and genital organ malformations)—may be linked to increased risks. However, these signals were based on a limited number of studies and should be interpreted with caution given variability in exposure definitions, study quality, and potential residual confounding.</div></div><div><h3>Conclusions</h3><div>For women undergoing assisted reproduction or those at increased risk of miscarriage, certain herbal medicines may offer potential benefits during pregnancy. Overall, evidence from RCTs and adjusted observational studies does not indicate a clear increase in adverse offspring outcomes associated with prenatal herbal medicine use. Nonetheless, a few herbs have been linked to potential safety concerns, although the supporting evidence remains limited and heterogeneous. Cautious use is advised, particularly for products without robust data on fetal and long-term postnatal safety.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108092"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948872","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":"YBX1-LDHB axis orchestrates pyruvate production from lactate to promote ICC initiation and development","authors":"Yong Liu ,&nbsp;Fei Wang ,&nbsp;Mi Zhang ,&nbsp;Xiabing Shi ,&nbsp;Lei Li ,&nbsp;Tingjie Wang ,&nbsp;Haifeng Zhang ,&nbsp;Zhongyu Cheng ,&nbsp;Xiangpan Li ,&nbsp;Juan Chen ,&nbsp;Chuanrui Xu","doi":"10.1016/j.phrs.2026.108110","DOIUrl":"10.1016/j.phrs.2026.108110","url":null,"abstract":"<div><div>Previous work from our group established that Y-box binding protein 1 (YBX1) plays a pivotal role in the initiation and progression of intrahepatic cholangiocarcinoma (ICC); however, its specific biological functions and underlying regulatory mechanisms remain unclear. The current study demonstrates that YBX1 is highly expressed in ICC tissues, and its highly expression correlates significantly with a poor prognosis in patients with ICC. <em>In vitro</em> experiments revealed that YBX1 overexpression significantly enhanced the proliferation of ICC cells. Conversely, YBX1 knockout robustly inhibited tumor growth in both <em>in vitro</em> and <em>in viv</em>o models. Mechanistically, YBX1 upregulated the expression of lactate dehydrogenase B (LDHB) by increasing its transcriptional activity and stabilizing LDHB mRNA. Elevated LDHB expression drives the conversion of lactate to pyruvate, which is further metabolized to acetyl coenzyme A. This metabolic reprogramming enhances the activity of tricarboxylic acid (TCA) cycle and production of adenosine triphosphate, thereby providing essential energy support for the proliferation of ICC cells. Corroboratively, inhibiting LDHB <em>via</em> CRISPR-Cas9-mediated knockout suppressed ICC cell proliferation, whereas LDHB overexpression accelerated the ICC tumor progression. Lactate induces YBX1 nuclear translocation, which in turn activates LDHB transcription. Collectively, our findings demonstrate the oncogenic roles of YBX1 and LDHB in ICC progression, identify lactate as a key energy source sustaining the activity of TCA cycle and oxidative phosphorylation, and highlight the YBX1-LDHB axis as a potential therapeutic target.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108110"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038222","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":"Reply to letter to the editor questions and comments on “ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation”","authors":"Juan Wang,&nbsp;Hui Tao,&nbsp;Chao Lu,&nbsp;Jingjing Yang","doi":"10.1016/j.phrs.2026.108102","DOIUrl":"10.1016/j.phrs.2026.108102","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108102"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019228","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":"Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects","authors":"Hao-wen Lin ,&nbsp;Shi-pian Li ,&nbsp;Jia-xin Wen ,&nbsp;Jia-xuan Zhang ,&nbsp;Bi-meng Zhang ,&nbsp;Yong-jun Wang ,&nbsp;Xue-jun Cui ,&nbsp;Min Yao","doi":"10.1016/j.phrs.2025.108074","DOIUrl":"10.1016/j.phrs.2025.108074","url":null,"abstract":"<div><div>Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from <em>Panax notoginseng</em> (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108074"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800202","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":"Response letter to Chi-Tung Lu et al.’s Comment on “Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China”","authors":"Yu Zhang,&nbsp;Yingjie Wang","doi":"10.1016/j.phrs.2026.108086","DOIUrl":"10.1016/j.phrs.2026.108086","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108086"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918201","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":"Study on epigenetic regulatory mechanism of MBD4 with a germline loss-of-function mutation (rs140693) responsible for retinoblastoma chemoresistance via the cell cycle and apoptotic pathways","authors":"Li Zhang ,&nbsp;Wenping Song ,&nbsp;Junting Wang ,&nbsp;Yelin Zhao ,&nbsp;Chenyu Yuan ,&nbsp;Zhilong Ruan ,&nbsp;Jiaqi Chen ,&nbsp;Junyang Zhao ,&nbsp;Hongjuan Yao ,&nbsp;Hebing Chen ,&nbsp;Chengyue Zhang ,&nbsp;Liang Li","doi":"10.1016/j.phrs.2026.108098","DOIUrl":"10.1016/j.phrs.2026.108098","url":null,"abstract":"<div><div>Recurrence of high-risk advanced retinoblastoma (RB) is still a major obstacle even after enucleation due to resistance to adjuvant chemotherapy, especially in China. To identify any germline alterations or candidate genes associated with RB prognosis, we obtained whole-exome sequencing (WES) and reduced-representation bisulfite sequencing (RRBS) profiles by using patient peripheral blood samples, followed by clinical validation and functional characterization. For follow-up studies, we selected 17 candidate genes from the WES and RRBS analyses. Among them, <em>MBD4</em>, which carries a germline loss-of-function mutation (rs140693), was identified for further clinical replication. MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. There were marked decreases in the expression of 5 related genes plus increased DNA methylation in their promoters in Y79 (MBD4^-/-) cells, along with even more significant effects after carboplatin treatment. MBD4 affected the transcription and expression of its downstream genes, such as FADD and P21, via MBDCap-PCR, ChIP<img>qPCR, and reporter gene assays. Moreover, the germline mutation was responsible for MBD4 instability with attenuated binding to USP7, thereby leading to impaired drug sensitivity. It was confirmed by the reinstated susceptibility of Y79 (MBD4^-/-) cells after MBD4-WT was restored. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108098"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980180","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}