Molecular Pharmacology最新文献

{"title":"Bryostatins 1 and 3 inhibit TRPM8 and modify TRPM8- and TRPV1-mediated lung epithelial cell responses to a proinflammatory stimulus via protein kinase C.","authors":"Lili Sun, John G Lamb, Changshan Niu, Samantha N Serna, Erin Gail Romero, Cassandra E Deering-Rice, Eric W Schmidt, Martin Golkowski, Christopher A Reilly","doi":"10.1016/j.molpha.2025.100042","DOIUrl":"10.1016/j.molpha.2025.100042","url":null,"abstract":"<p><p>Bryostatin 1 is a protein kinase C (PKC α, β, δ) activator with anti-inflammatory effects. We hypothesized that bryostatins 1 and 3 could modulate transient receptor potential (TRP) channels via PKC and alter TRP-mediated proinflammatory signaling in lung epithelial cells challenged with a proinflammatory stimulus, coal fly ash (CFA). Bryostatins 1 and 3 inhibited icilin-induced calcium flux in HEK-293 cells overexpressing full-length human transient receptor potential melastatin-8 (TRPM8) but did not inhibit activation by menthol or the activities of human transient receptor potential ankyrin 1, transient receptor potential vanilloid 1 (TRPV1), TRPV3, or TRPV4; mouse and rat TRPM8 were less sensitive to inhibition. TRPM8 inhibition was transient (<24 hours), PKC-dependent, and involved differential phosphorylation of amino acids T17, S27, S850, and S1040. CFA particles stimulate interleukin-8 (IL8) and C-X-C motif chemokine ligand 1 (CXCL1) expression by human bronchial epithelial cells via activation of truncated TRPM8 (TRPM8-Δ801) and TRPV1. However, bryostatins 1 and 3 altered IL8 and CXCL1 mRNA expression with and without CFA treatment. At 4 hours, the bryostatins also suppressed TRPM8 mRNA and induced TRPV1 mRNA, which reversed at 24 hours. These effects were reversed by pharmacological inhibition of PKC isoforms (α, ζ, ε, or η) but not δ, implying a network comprised of presumably PKCα, TRPM8-Δ801, and TRPV1 that regulates IL8 and CXCL1 expression by airway epithelial cells. Finally, an unexpected interaction between TRPV1 and TRPM8, but not TRPM8-Δ801, was also identified. Specifically, the coexpression of TRPM8 and TRPV1 reduced TRPM8 expression and activity, which was reversed by TRPV1 inhibition, revealing novel mechanisms by which bryostatins and PKC affect TRP channel signaling in lung epithelial and potentially other cell types. SIGNIFICANCE STATEMENT: Bryostatins 1 and 3 selectively and transiently inhibit human TRPM8 activity via protein kinase C-dependent phosphorylation and temporally modify the expression and induction of interleukin-8 and C-X-C motif chemokine ligand 1 in lung epithelial cells by regulating TRPV1 and TRPM8 expression. This regulatory nexus may have therapeutic potential for treating airway inflammation.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100042"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research approaches for exploring the hidden conversations of G protein-coupled receptor transactivation.","authors":"Janbolat Ashim, Min Jae Seo, Sangho Ji, Joongyu Heo, Wookyung Yu","doi":"10.1016/j.molpha.2025.100043","DOIUrl":"10.1016/j.molpha.2025.100043","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) signaling is a crucial physiological mechanism that encompasses a wide range of signaling phenomena. Although traditional GPCR signaling involves G protein or arrestin-related activation, other modes such as biphasic activation, dimer or oligomeric activation, and transactivation have also been observed. Herein, we focus on the increasingly recognized process of GPCR-transactivation. Transactivation refers to the ability of GPCRs to activate other receptor types, especially receptor tyrosine kinases, without engaging their own specific ligands. This cross-talk between GPCRs and other receptors facilitates the integration of multiple signaling pathways, thereby regulating diverse cellular responses, which underscores its physiological significance. In this review, we provide a comprehensive overview of the role of GPCR-transactivation in physiology. We also discuss the growing interest in this field and examine the various tools available for studying transactivation. Additionally, we highlight recent advancements in emerging tools and their application to GPCR-transactivation research. Finally, we propose future research directions and consider the potential impact of new technologies in this rapidly evolving field. SIGNIFICANCE STATEMENT: G protein-coupled receptor transactivation plays a key role in integrating multiple signaling pathways by activating other proteins, like receptor tyrosine kinases, without binding their specific ligands. Here, we focus on the significance of transactivation and the various approaches used to study this phenomenon.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100043"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special section: William A. Catterall Memorial Issue - Mechanisms of Electrical Excitability.","authors":"Lori L Isom","doi":"10.1016/j.molpha.2025.100044","DOIUrl":"10.1016/j.molpha.2025.100044","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100044"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fat traffic control: S-acylation in axonal transport.","authors":"Amelia H Doerksen, Nisandi N Herath, Shaun S Sanders","doi":"10.1016/j.molpha.2025.100039","DOIUrl":"10.1016/j.molpha.2025.100039","url":null,"abstract":"<p><p>Neuronal axons serve as a conduit for the coordinated transport of essential molecular cargo between structurally and functionally distinct subcellular compartments via axonal molecular machinery. Long-distance, efficient axonal transport of membrane-bound organelles enables signal transduction and neuronal homeostasis. Efficient axonal transport is conducted by dynein and kinesin ATPase motors that use a local ATP supply from metabolic enzymes tethered to transport vesicles. Molecular motor adaptor proteins promote the processive motility and cargo selectivity of fast axonal transport. Axonal transport impairments are directly causative or associated with many neurodegenerative diseases and neuropathologies. Cargo specificity, cargo-adaptor proteins, and posttranslational modifications of cargo, adaptor proteins, microtubules, or the motor protein subunits all contribute to the precise regulation of vesicular transit. One posttranslational lipid modification that is particularly important in neurons in regulating protein trafficking, protein-protein interactions, and protein association with lipid membranes is S-acylation. Interestingly, many fast axonal transport cargos, cytoskeletal-associated proteins, motor protein subunits, and adaptors are S-acylated to modulate axonal transport. Here, we review the established regulatory role of S-acylation in fast axonal transport and provide evidence for a broader role of S-acylation in regulating the motor-cargo complex machinery, adaptor proteins, and metabolic enzymes from low-throughput studies and S-acyl-proteomic data sets. We propose that S-acylation regulates fast axonal transport and vesicular motility through localization of the proteins required for the motile cargo-complex machinery and relate how perturbed S-acylation contributes to transport impairments in neurological disorders. SIGNIFICANCE STATEMENT: This review investigates the regulatory role of S-acylation in fast axonal transport and its connection to neurological diseases, with a focus on the emerging connections between S-acylation and the molecular motors, adaptor proteins, and metabolic enzymes that make up the trafficking machinery.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100039"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 \"The Natural Compound Withaferin A Covalently Binds to Cys239 of β-Tubulin to Promote Tubulin Degradation\".","authors":"","doi":"10.1016/j.molpha.2025.100045","DOIUrl":"10.1016/j.molpha.2025.100045","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100045"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoprenaline shows unique kinase dependencies in stimulating β₁AR-β-arrestin2 interaction compared to endogenous catecholamines.","authors":"Edda S F Matthees, Luca E Kletzin, Arnelle Löbbert, Jana S Hoffmann, Carolin Große, Alvar D Gossert, Carsten Hoffmann","doi":"10.1016/j.molpha.2025.100041","DOIUrl":"10.1016/j.molpha.2025.100041","url":null,"abstract":"<p><p>The β1-adrenergic receptor (β₁AR) is an essential G protein-coupled receptor in the heart. Its dysregulation represents a hallmark of cardiac diseases. Studies have identified a unique mode of β-arrestin interaction, where β₁AR briefly engages with β-arrestins before catalytically accumulating them at the plasma membrane (PM) independently of the receptor. Although receptor phosphorylation crucially impacts β-arrestins, the contributions of specific kinases vital in β₁AR regulation remain unclear. Here, we employed G protein-coupled receptor kinase (GRK) GRK2/3/5/6 knockout cells and the protein kinase A inhibitor H89 in bioluminescence resonance energy transfer-based assays to systematically assess GRKs and protein kinase A in direct β-arrestin2 recruitment to β₁AR and β-arrestin2 translocation to the PM. Furthermore, we compared the effects of the synthetic agonist isoprenaline with the endogenous catecholamines: epinephrine and norepinephrine. We observed pronounced differences in their kinase dependencies to mediate β-arrestin2 translocation to the PM. Upon isoprenaline stimulation, GRKs strongly influenced β-arrestin2 translocation to the PM but had no effect on direct β-arrestin2 recruitment to β₁AR. Additionally, in a GRK2-specific context, protein kinase A inhibition primarily reduced the efficacy of isoprenaline for β-arrestin2 translocation, whereas for GRK5, it decreased potency. Strikingly, these kinase-dependent effects were absent for epinephrine and norepinephrine, suggesting distinct underlying molecular mechanisms for β-arrestin2 accumulation at the PM. This observation could be explained by agonist-specific differences in receptor conformational rearrangements, as suggested by distinct changes in the NMR spectra of β₁AR. Our findings highlight that synthetic and endogenous ligands induce distinct molecular mechanisms in β₁AR regulation, emphasizing the need to consider these differences when translating molecular insights into physiological contexts. SIGNIFICANCE STATEMENT: Our findings reveal mechanistic differences in β1-adrenergic receptor-mediated catalytic activation of β-arrestin2 by synthetic and endogenous agonists, driven by distinct G protein-coupled receptor kinases and protein kinase A dependencies. Although β-arrestin2 translocation to the PM occurred to similar extents with isoprenaline, epinephrine, and norepinephrine, kinase involvement was crucial only upon Iso stimulation of β1-adrenergic receptor. By elucidating these ligand-specific pathways, this study advances our understanding of β1-adrenergic receptor signaling and regulation while additionally highlighting the importance of considering these differences when translating molecular insights into pathophysiological contexts.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100041"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and cellular effects of hydroxy-1,4 naphthoquinones used in dermatological and cosmetic applications on human protein tyrosine phosphatase PTP1B in human keratinocytes.","authors":"Tessa Arnaud, Christina Michail, Joséphine Gudin de Vallerin, Huicong Liang, Ximing Xu, Julien Dairou, Kevin Cariou, Jean-Marie Dupret, Mireille Viguier, Fernando Rodrigues-Lima, Frédérique Deshayes","doi":"10.1016/j.molpha.2025.100050","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100050","url":null,"abstract":"<p><p>The hydroxy-1,4-naphthoquinones-lawsone, juglone, and plumbagin-widely used in dermatological and cosmetic applications, exhibit a broad spectrum of biological activities, including notable cytotoxic effects. Of the various cellular processes these quinones influence, signaling pathways hold utmost significance. This study elucidates the impact of lawsone, juglone, and plumbagin on a key tyrosine phosphatase, PTP1B, in vitro or within keratinocyte cell lines. Additionally, we assessed the phosphorylation status of EGFR and its subsequent consequences on cell migration. Our results reveal that juglone and plumbagin, but not lawsone, irreversibly inhibit PTP1B enzyme activity by up to 75% through modification of its catalytic cysteine 215 residue. These quinones also lead to an average of 3-fold increase in EGFR phosphorylation. These findings offer new insights into the molecular mechanisms through which hydroxy-1,4-naphthoquinones of dermatological or cosmetic interest modulate critical signaling pathways. SIGNIFICANCE STATEMENT: Hydroxy-1,4-naphthoquinones such as lawsone, juglone, and plumbagin are widely used in dermatological applications, yet their precise molecular and cellular effects remain underexplored. This study reveals that juglone and plumbagin irreversibly inhibit the phosphatase PTP1B by targeting its catalytic cysteine, leading to enhanced EGFR phosphorylation. These findings provide critical insights into how these compounds modulate key signaling pathways, advancing our understanding of their potential therapeutic applications in skin repair and diseases involving dysregulated cell signaling.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100050"},"PeriodicalIF":3.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atraric acid increases the antitumor effect of BRAF inhibitor through the regulation of the HGK/MEK1/ERK signaling pathway.","authors":"Ming Yao, Cheng-Yun Huang, Bai-Hui Lu, Sheng-Ping Jiang, Jing Li, Xiao-Long Yang","doi":"10.1016/j.molpha.2025.100049","DOIUrl":"10.1016/j.molpha.2025.100049","url":null,"abstract":"<p><p>Malignant melanoma is the most aggressive and deadly skin cancer. Conventional treatment drugs, such as vemurafenib, are prone to resistance, resulting in very low patient survival. This study probed into the antitumor potential of coadministration of atraric acid (AA), a natural compound derived from lichens with multiple biological activities, and vemurafenib in melanoma. Our findings revealed that AA enhances vemurafenib's ability to reduce viability and induce apoptosis in B16-F10 melanoma cells. In vivo studies, including histological analysis, showed that the combination of AA and vemurafenib effectively inhibited melanoma growth and metastasis with minimal side effects. Inhibition of tumor growth by vemurafenib in the presence of AA increased from 20.11% to 23.93% (low dose AA) and 52.06% (high dose AA). Transcriptomic analysis, quantitative reverse transcription polymerase chain reaction, and western blot indicated that AA enhances the antimelanoma effect of vemurafenib was mediated through the modulation of hematopoietic progenitor kinase 1 (HGK), MAP kinase kinase 1 (MEK1), and extracellular signal-regulated kinase (ERK) expression. Molecular docking studies suggested that AA might reduce the expression of MEK1 and ERK by suppressing the phosphorylation of HGK, thereby enhancing vemurafenib inhibition of melanoma growth and metastasis. In conclusion, our study presents AA as a promising candidate that may help enhance the antimelanoma activity of vemurafenib, offering a new avenue for clinical cancer treatment. SIGNIFICANCE STATEMENT: The combination of atraric acid and vemurafenib effectively inhibited melanoma growth and metastasis with minimal side effects. The synergistic effect of atraric acid and vemurafenib is achieved by suppressing the phosphorylation of HGK to reduce the expression of MEK1 and ERK. Atraric acid is a promising candidate in combating chemoresistance in melanoma therapy.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100049"},"PeriodicalIF":3.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulating vascular endothelial K_Ca2.3 channels alleviates pulmonary hypertension in mice.","authors":"Meng-Zhuan Han, Yan Wang, Ke-Xin Sun, Yong-Jian Zhang, Ru-Yue Bai, Lin-Hong Wu, Xia-Xia Hai, Bao-Chang Lai, Jing-Jing Li, Gang She, Yi Zhang, Xiao-Jun Du, Zheng-Da Pang, Xiu-Ling Deng","doi":"10.1016/j.molpha.2025.100048","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100048","url":null,"abstract":"<p><p>Endothelial dysfunction of pulmonary arteries is important in the initiation of pulmonary hypertension (PH). Pulmonary vascular tone is regulated by endothelium-dependent hyperpolarization (EDH) that induces vasodilation. Although K_Ca2.3 channels are involved as a key initiator of EDH response, therapeutic potential of endothelial K_Ca2.3 channels in PH remains unclear. Bioinformatic and biochemical analyses were used to explore K_Ca2.3 expression in patients with PH. Two mouse PH models were created by injection of Sugen 5416 plus hypoxia or injection with monocrotaline. Endothelial-specific K_Ca2.3 adeno-associated virus (AAV-Kcnn3) was constructed, and the efficacy in both PH models was tested using immunohistochemistry, myograph system, and echocardiography. Expression of K_Ca2.3 was decreased in pulmonary arterial endothelial cells or lung tissues from patients with PH and both experimental PH models. AAV-Kcnn3 treatment increased K_Ca2.3 expression in pulmonary endothelium and ameliorated K_Ca2.3-medieated vasodilation of small pulmonary arteries and pulmonary vascular endothelial dysfunction in both PH models. The key PH phenotypes, including elevated right ventricular pressure, Fulton index, pulmonary artery wall thickness, and the free wall thickness of the right ventricle, were remarkably alleviated by AAV-Kcnn3 treatment in both PH models. In conclusion, augmented expression of endothelium-specific K_Ca2.3 channels markedly inhibits the development of PH by improving endothelium-dependent relaxation. SIGNIFICANCE STATEMENT: This study demonstrated downregulated expression of K_Ca2.3 channels in lung tissues, specifically in pulmonary artery endothelial cells from patients or mice with pulmonary hypertension. Upregulation of endothelial K_Ca2.3 might serve as a therapeutic strategy in the early-stage pulmonary hypertension.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100048"},"PeriodicalIF":3.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclovirobuxine inhibits ferroptosis to mitigate Alzheimer disease in glutamate-induced SH-SY5Y cell: the role of the liquid-liquid phase separation of FTH1.","authors":"Fuwei Wang, Qiong Zhou, Zihao Chen, Lihua Xie, Nan Zheng, Ziwen Chen, Qiang Sun, Jikun Du, Jiantao Lin, Baohong Li, Li Li","doi":"10.1016/j.molpha.2025.100046","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100046","url":null,"abstract":"<p><p>Ferroptosis represents a distinct form of cell death that differentiates it from conventional apoptosis. Numerous studies have demonstrated that ferroptosis holds significant potential for elucidating neuronal damage in Alzheimer disease (AD). In addition, liquid-liquid phase separation has emerged as a significant biological process in recent years. It plays a crucial role in the regulation of various proteins in vivo and is closely associated with ferroptosis. Meanwhile, nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a crucial signaling pathway in ferroptosis and plays a significant role in regulating many key components of the ferroptosis pathway. In addition, an increasing volume of research is being conducted on natural medicines aimed at enhancing the treatment of AD. Cyclovirobuxine (Cyc) is an alkaloid compound extracted from the traditional Chinese medicinal plant, boxwood. It has demonstrated therapeutic potential in the treatment of neurodegenerative diseases. Therefore, in this study, we established an AD cell model using glutamate-induced SH-SY5Y. In glutamate-induced SH-SY5Y cells, Cyc treatment significantly improved mitochondrial function and effectively inhibited lipid peroxidation and restored the downregulation of FTH1 levels induced. Furthermore, Cyc treatment activated the Nrf2 signaling pathway, significantly elevated the nuclear levels of Nrf2, and inhibited both iron deposition and lipid peroxidation. Cyc treatment conferred resistance to ferroptosis in erastin-stimulated SH-SY5Y cells, wherein the Nrf2 signaling pathway and FTH1 protein play crucial roles. The collective findings presented here underscore the protective mechanism of action of Cyc in AD and emphasize its potential as a therapeutic agent for AD treatment. SIGNIFICANCE STATEMENT: It reveals at the cellular level the mechanism by which cyclovirobuxine improves Alzheimer disease through the inhibition of ferroptosis, providing a novel approach and strategy for the treatment of patients with Alzheimer disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100046"},"PeriodicalIF":3.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}