Pharmacological research最新文献

{"title":"Pterostilbene alleviates doxorubicin-induced cardiotoxicity by inhibiting cardiomyocytes pyroptosis mediated by the IL-6/STAT3-caspase-3/GSDME axis and M1 polarization of macrophages","authors":"Xiaoxia Huang ,&nbsp;Yuelei Chen ,&nbsp;Yanan Zhang ,&nbsp;Xinyi Hu ,&nbsp;Wenhui Yang ,&nbsp;Tingting Pan ,&nbsp;Wei Gao ,&nbsp;Kidong Eom ,&nbsp;Peng Chen ,&nbsp;Jing Dong ,&nbsp;Lin Li","doi":"10.1016/j.phrs.2026.108129","DOIUrl":"10.1016/j.phrs.2026.108129","url":null,"abstract":"<div><div>Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major dose-limiting complication of chemotherapy, in which pyroptosis is considered a key pathological mechanism. The natural stilbene compound pterostilbene (PTE) has demonstrated cardioprotective potential, but its role in DOX-induced pyroptosis remains unclear. This study, using both <em>in vitro</em> H9C2 cardiomyocyte and <em>in vivo</em> C57BL/6 mouse models of DIC, confirmed that PTE effectively inhibits DOX-induced cardiomyocyte pyroptosis and alleviates cardiac injury. Mechanistically, DOX activates the IL-6/STAT3 signaling pathway, promoting the nuclear translocation of phosphorylated STAT3 (pSTAT3). CUT&amp;Tag and dual-luciferase reporter assays further revealed that activated STAT3 directly binds to the core promoter regions of the <em>caspase-3</em> and <em>Gasdermin E (GSDME)</em> genes, thereby upregulating their expression at the transcriptional level and ultimately activating the caspase-3/GSDME-mediated pyroptosis pathway. PTE effectively blocks this pyroptotic execution pathway by inhibiting the activation of the IL-6/STAT3 pathway. Furthermore, this study elucidated a critical interaction between cardiomyocytes and immune cells: GSDME-mediated cardiomyocyte pyroptosis releases various soluble factors, with IL-6 being a key cytokine that drives the polarization of macrophages toward the pro-inflammatory M1 phenotype, thereby amplifying the myocardial inflammatory response. By inhibiting cardiomyocyte pyroptosis, particularly by reducing IL-6 release, PTE effectively interrupts this “cardiomyocyte pyroptosis-M1 macrophage polarization” vicious cycle and restores myocardial homeostasis. In summary, our research elucidates a signaling cascade driving DOX-induced cardiotoxicity: IL-6/STAT3-caspase-3/GSDME. We confirmed that PTE is an effective inhibitor of this pathway, not only directly protecting cardiomyocytes but also suppressing the subsequent pyroptosis-driven inflammatory response, thereby highlighting its significant therapeutic potential in mitigating DIC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108129"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137765","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 SAM-m6A axis as an unexplored therapeutic hub for plant-derived regulation of disease metabolism","authors":"Yuxuan Zhao ,&nbsp;Jingyimei Liang ,&nbsp;Wanning Ma ,&nbsp;Jianbo Xiao ,&nbsp;Hui Cao","doi":"10.1016/j.phrs.2026.108114","DOIUrl":"10.1016/j.phrs.2026.108114","url":null,"abstract":"<div><div>S-adenosylmethionine (SAM) is the main cellular methyl donor and a core product of one-carbon metabolism. Its balance with S-adenosylhomocysteine (SAH) defines methylation potential and shapes epigenetic and epitranscriptomic outputs. RNA N⁶-methyladenosine (m⁶A) directly depends on SAM and is controlled by a writer-reader-eraser system. This review summarizes how altered SAM supply, SAH accumulation, and shifts in the SAM/SAH ratio can reprogram m⁶A landscapes. These changes can occur in cancer, metabolic disease, inflammation, and neurodegeneration. We integrate metabolic control of SAM generation and consumption with regulation of METTL3/METTL14, WTAP and related cofactors, and the erasers FTO and ALKBH5. We also assess plant-derived bioactive compounds proposed to act on this coupling. Most phytochemicals do not behave as potent, selective m⁶A enzyme inhibitors. They more often act upstream by reshaping one-carbon metabolism, redox state, and protein expression. This profile contrasts with canonical synthetic inhibitors that block a single node with higher affinity and more predictable pharmacodynamics. Together, the evidence supports the SAM-m⁶A axis as a practical framework to connect nutrient state with RNA fate decisions. It also highlights key gaps for translation, including target engagement, dose-exposure alignment, and causal validation of m⁶A-dependent phenotypes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108114"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081503","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":"Inhibition of Kdm2a with Daminozide suppresses high myopia progression and related neuropsychiatric comorbidities by epigenetically modulating the gut-eye axis","authors":"Zixuan Li ,&nbsp;Hao Li ,&nbsp;Shibo Zhang ,&nbsp;Xixi Wang ,&nbsp;Xinpei Ji ,&nbsp;Jianping Zhang ,&nbsp;Dengyong Hou ,&nbsp;Mengya Fan ,&nbsp;Ruisang Liu ,&nbsp;Yan Xiang ,&nbsp;Yuyu Jiang ,&nbsp;Yingying Ding ,&nbsp;Yanbin Zhan ,&nbsp;Liben Fang ,&nbsp;Bin Sun ,&nbsp;Huafei Li ,&nbsp;Xingguang Liu ,&nbsp;Yunkai Zhang ,&nbsp;Xiaomeng Ren","doi":"10.1016/j.phrs.2026.108137","DOIUrl":"10.1016/j.phrs.2026.108137","url":null,"abstract":"<div><div>High myopia (HM) poses a growing public health challenge due to its increasing prevalence and the associated risks of blinding complications and psychological comorbidities. While traditionally considered an isolated ocular condition, emerging evidence implicates systemic mechanisms, notably through the gut–eye axis and immune factors, play important part in the pathogenesis of HM. Histone demethylase Kdm2a, the key H3K36me2 modification eraser, is critically involved in various inflammatory diseases, yet its specific role in the gut–eye axis and HM remains elusive. To address this, the HM model was successfully established. HM mice exhibited significant scleral thinning, reduced collagen protein, and prominent anxiety-like behaviors. Crucially, they were suffering from gut microbial dysbiosis and intestinal barrier impairment. Intriguingly, upregulated Kdm2a and correspondingly decreased H3K36me2 levels were observed in the intestinal epithelial cells (IECs) of HM mice. Treatment with Daminozide (DA), the selective inhibitor of Kdm2a, effectively suppressed myopia progression and ameliorated psychological comorbidities. Mechanistically, DA restored gut microbiota homeostasis, colonic morphology, and barrier integrity. The transcriptomic profiling further revealed the protective effects of Kdm2a inhibition on modulating key pathways involved in intestinal inflammation and tissue remodeling. Collectively, this work elucidates a novel gut–eye pathway in HM pathogenesis and identifies Kdm2a in IECs as a promising therapeutic target for HM and its associated psychological comorbidities.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108137"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207157","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":"Semaglutide attenuates autistic-like behaviors in BTBR mice through the shaping of gut microbiota","authors":"Jiayin Liu ,&nbsp;Tianyao Liu ,&nbsp;Lina Nie ,&nbsp;Lianyu Zhou ,&nbsp;Jing Luo ,&nbsp;Li Guo ,&nbsp;Xinggao Zhang ,&nbsp;Meifeng Gong ,&nbsp;Zhenyang Chen ,&nbsp;Xin Li ,&nbsp;Xiaotang Fan","doi":"10.1016/j.phrs.2026.108149","DOIUrl":"10.1016/j.phrs.2026.108149","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental condition characterized by deficits in social communication and the presence of repetitive behaviors. The significance of the gut-brain axis in the pathogenesis of ASD often points to a relationship with gut dysbiosis and metabolic disruptions in affected individuals. This study investigates the potential of the glucagon-like peptide-1 receptor agonist, semaglutide, to modulate gut microbiota, metabolic pathways, and neurodevelopmental outcomes using the BTBR T(+) Itpr3(tf)/J (BTBR) mouse model of ASD. Our findings indicate that administration of semaglutide during an early neurodevelopmental stage leads to significant improvements in social behavior, cognitive function, and repetitive behaviors in BTBR mice. This therapeutic effect is associated with the restoration of gut microbiota, as demonstrated by fecal microbiota transplantation from C57BL/6 J controls and semaglutide-treated BTBR mice, which ameliorated the ASD behaviors in BTBR mice. Metabolomic profiling identified adrenic acid (AdA) as a crucial mediator; AdA levels in BTBR mice were lower but returned to normal following semaglutide treatment. Additionally, RNA sequencing revealed that hippocampal neurogenesis is associated with semaglutide treatment, and AdA supplementation restored social behaviors and hippocampal neurogenesis. These results highlight the critical role of the gut microbiota-brain axis in the therapeutic effects of semaglutide on ASD and suggest that targeting this axis alongside AdA may represent a promising strategy for ASD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108149"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271771","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":"Apoptosis and motor deficits in SPG76 hereditary spastic paraplegia: Calpain 2 inhibition as therapeutic strategy","authors":"Francesca Brivio ,&nbsp;Giulia Guarato ,&nbsp;Elena Panzeri ,&nbsp;Fiore Manganelli ,&nbsp;Massimiliano Filosto ,&nbsp;Chiara Vantaggiato ,&nbsp;Maria Teresa Bassi","doi":"10.1016/j.phrs.2026.108115","DOIUrl":"10.1016/j.phrs.2026.108115","url":null,"abstract":"<div><div>SPG76 is a complicated form of hereditary spastic paraplegia (HSP) associated with mutations in the <em>CAPN1</em> gene. The encoded protein, calpain 1, is a calcium-activated cysteine protease that catalyzes the proteolytic cleavage of a variety of cellular proteins and is involved in a wide range of biological processes. Calpain 1 and calpain 2 isoforms are highly expressed in various tissues and have opposite effects on survival: calpain 1 induces the activation of Akt and ERK pro-survival pathways, regulates autophagy and is neuroprotective, while calpain 2 induces neurodegeneration. We characterized fibroblast cells derived from two SPG76 patients carrying a homozygous mutation (p.Tyr320Leufs73*) in the <em>CAPN1</em> gene that leads to the absence of the protein. Loss of calpain 1 in SPG76 patient’s derived cells increased calpain 2 activation and induced autophagosome formation and accumulation, inhibited Akt and ERK1/2 pro-survival pathways, reducing GSK3β inhibition, and increased cell susceptibility to ER stress. In ER stress conditions, SPG76 cells presented unfolded protein response (UPR) activation, increased apoptosis and cell death. We analysed the potential of targeting calpain 2 and the Akt pro-survival pathway to rescue the SPG76 deranged pathways in patient’s derived cells. We found that the calpain inhibitors olesoxime and MDL28170, naringenin and the GSK3β inhibitor tideglusib were the most effective in increasing Akt activation and GSK3β inhibition and in rescuing apoptosis and cell death in SPG76 cells. Among these, olesoxime and MDL28170 reduced calpain activity, rescued apoptosis and locomotor deficits <em>in vivo</em> in a CalpB KO <em>Drosophila</em> model that replicates the SPG76 phenotype.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108115"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081502","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 novel peptide blocking CD93/IGFBP7 interaction normalizes tumor vessels and synergizes with radiotherapy for cancer immunotherapy","authors":"Yuzhen Qian ,&nbsp;Qiongqiong Zhang ,&nbsp;Yahong Wu ,&nbsp;Yixuan Sun ,&nbsp;Ying Cheng ,&nbsp;Peishang Shi ,&nbsp;Qingchao Wang ,&nbsp;Lu Qiu ,&nbsp;Mingshuang Wang ,&nbsp;Wenshan Zhao ,&nbsp;Wenjie Zhai ,&nbsp;Lingling Li","doi":"10.1016/j.phrs.2026.108118","DOIUrl":"10.1016/j.phrs.2026.108118","url":null,"abstract":"<div><div>The aberrant tumor vasculature fosters a permissive microenvironment that impedes immune effector cell infiltration and simultaneously promotes neoplastic progression. CD93 is an important target for antiangiogenic normalization therapy. Here, we found that the expression of CD93 and its ligand IGFBP7 were significantly upregulated in cancers and closely associated with various pro-angiogenic factors. Next, we identified the CD93 binding peptides (CBP). After systematic <span>D</span>-amino acid modification and retro-inversion, CBP-D8 peptide exhibited the highest blocking activity on CD93/IGFBP7 interaction, and potent inhibition on the migration of endothelial cells. Besides, CBP-D8 peptide significantly facilitated cytotoxic CD8⁺ T cells and NK cells infiltration through enhanced blood perfusion and increased coverage of pericytes and vascular smooth muscle cells. More importantly, CBP-D8 peptide combined with radiotherapy significantly abrogated tumor growth and elicited systemic antitumor immune response. Our study identified a novel peptide blocking CD93/IGFBP7 interaction to normalize tumor vascular function, as well as revealed an approach to promote a favorable tumor microenvironment for the therapeutic intervention.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108118"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106790","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":"Agrin at the crossroads of aging: A pleiotropic regulator in age-related diseases","authors":"Jiayu Yuan ,&nbsp;Shun Zhang ,&nbsp;Dong Han ,&nbsp;Xiaoyu Dong","doi":"10.1016/j.phrs.2026.108131","DOIUrl":"10.1016/j.phrs.2026.108131","url":null,"abstract":"<div><div>Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer’s disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ‘‘double-edged sword’’ characteristic across different disease stages or tissue contexts—exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108131"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137794","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":"Mechanistic Rationale of Seladelpar’s Clinical Efficacy through the Selective PPAR-δ Activation in Primary Biliary Cholangitis","authors":"Alessio Gerussi ,&nbsp;Matteo Fornai","doi":"10.1016/j.phrs.2026.108144","DOIUrl":"10.1016/j.phrs.2026.108144","url":null,"abstract":"<div><div>Seladelpar is a selective PPAR-δ agonist approved for the treatment of the rare cholestatic disease Primary Biliary Cholangitis, in patients who do not achieve adequate biochemical control with first-line therapy. This review outlines the characteristics of PPAR-δ, with insights into its activity across different tissues, and summarizes the pharmacology of Seladelpar, providing the background for the subsequent discussion of its clinical efficacy and safety in humans.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108144"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228044","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":"Comment on “Plasma miR-150-5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: A long-term prospective longitudinal study”","authors":"Shanshan Ru,&nbsp;Yingzhe Zhang","doi":"10.1016/j.phrs.2026.108117","DOIUrl":"10.1016/j.phrs.2026.108117","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108117"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097419","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":"Targeting FoxO1 in cardiovascular diseases: Mechanisms and therapeutic potential","authors":"Xue Wu ,&nbsp;Xia Du ,&nbsp;Chenxi Lu","doi":"10.1016/j.phrs.2026.108122","DOIUrl":"10.1016/j.phrs.2026.108122","url":null,"abstract":"<div><div>Cardiovascular Disease (CVDs), as a major life-threatening disease, has attracted worldwide attention. Seeking novel and effective therapeutic strategies is still among the important in the cardiovascular field. Forkhead box O (FoxO) family comprises a group of transcription factors with highly conserved structures that have a major role in a plethora of biological functions. Recently, a considerable amount of research has shown the physiological and pathological roles of Fox family (especially FoxO1) in CVDs (including myocardial ischemia-reperfusion injury, myocardial hypertrophy, myocardial infarction, myocardial fibrosis, cardiomyopathy, and atherosclerosis), and they affect the plasticity, stress response, and metabolism of the heart by regulating various signaling pathways and biological functions. In this review, we outline the structure of the Fox family and FoxO1. Next, we summarize the various pathological and physiological mechanisms of FoxO1 (inflammation, oxidative stress, autophagy, endothelial dysfunction, lipid metabolism and angiogenesis), as well as the regulatory style of FoxO1 (phosphorylation, methylation, ubiquitination and acetylation). Finally, we also reviewe the latest research advancements and potential future research directions concerning FoxO1 regulators in CVDs, laying the foundation for its transformation into a new and powerful clinical application.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108122"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097490","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}