Letters in Drug Design & Discovery最新文献

{"title":"Uncovering celecoxib’s anti-breast cancer mechanisms through network pharmacology, molecular docking, and dynamics","authors":"Wennan Huang, Zeming Yan, Yuzhou Wang, Zhenglu Chen, Xiangfeng Yang","doi":"10.1016/j.lddd.2025.100164","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100164","url":null,"abstract":"Celecoxib has gained attention as a potential anti-tumor agent in breast cancer. This study systematically elucidated the therapeutic mechanisms of celecoxib in this malignancy. The candidate targets of celecoxib and the molecular targets associated with breast cancer were retrieved. The protein-protein interaction (PPI) networks were established. GO and KEGG pathway enrichment analyses were performed. Molecular docking simulations and normal mode analysis (NMA) were used. This study identified 104 candidate targets of celecoxib, 18,389 potential targets implicated in breast cancer, and 95 overlapping targets. GSK3B, CCND1, PTGS2, CDK2, CDK4, and MTOR were identified as key hub proteins in celecoxib’s anti-breast cancer activity. These overlapping candidates were associated with protein serine/threonine kinase activity and cyclin-dependent protein kinase regulator activity and involved in FoxO, prolactin, p53, and PI3K-Akt pathways. Celecoxib exhibited high binding affinity for GSK3B, CDK4, and MTOR, while showing moderate binding affinity for CDK2. Dynamic simulations revealed stable binding, minimal structural perturbations, and system-dependent rigidity profiles of the docked celecoxib-protein complexes. In vitro experimental results showed that celecoxib suppressed cell colony formation, migration, and invasion and enhanced apoptosis in MCF-7 cells by downregulating MTOR. This study suggests that celecoxib may exert anti-cancer effects in breast cancer via multiple targets (e.g., MTOR) and pathways.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 10","pages":"100164-100164"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147905308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide HDP15 protects against cognitive impairment after ischemia-reperfusion injury by regulating PRKN-mediated mitochondrial autophagy","authors":"Shujin He, Dandan Cheng, Yan Li, Yuanhong Liu, Qianru Chen, Hao Ding, Yang Yang, Hua Shen, Yiwen Li, Yan Chen, Huiwen Mao","doi":"10.1016/j.lddd.2025.100173","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100173","url":null,"abstract":"Post-stroke cognitive impairment (PSCI) involves complex pathophysiology and lacks specific therapeutic approaches. Synaptic plasticity and mitochondrial dysfunction are key pathological mechanisms in PSCI, with mitochondrial autophagy playing a crucial role in maintaining cellular homeostasis. HDP15 is an active, highly conserved peptide secreted by hippocampal neurons. While it is associated with synaptic plasticity, its effects on PSCI remain unknown. To investigate the effects of HDP15 on cognitive impairment following ischemia-reperfusion injury and explore its potential mechanisms. The cerebral middle artery occlusion (MCAO) model was used to evaluate HDP15's impact on neurological function and spatial cognition in rats. Oxygen-glucose deprivation reperfusion (OGD/R) experiments were conducted to study HDP15's regulatory effects on cell viability and mitochondrial function. Results: HDP15 significantly reduced neurological deficits in MCAO rats, shortened escape latency in the Morris water maze, and increased platform crossing attempts, demonstrating marked improvement in spatial cognition. HDP15 enhanced survival rates of OGD/R-treated SH-SY5Y cells, decreased lactate dehydrogenase (LDH) leakage, and upregulated expression of PSD-95, SYP, and α-synuclein. Additionally, HDP15 enhanced mitochondrial function by increasing basal respiration, maximal respiration, and ATP production, while promoting clearance of damaged mitochondria via PRKN-mediated autophagy. HDP15 significantly protects against ischemic stroke by regulating PRKN-mediated mitochondrial autophagy, thereby identifying a new potential target for PSCI treatment.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 10","pages":"100173-100173"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147913236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative network pharmacology and machine learning identify NLRP3 as a critical therapeutic target for liensinine in acute myocardial infarction","authors":"Xiaohai Huang, Dongping Li, Quanming Zhou, Zhumei Chen","doi":"10.1016/j.lddd.2025.100190","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100190","url":null,"abstract":"Acute myocardial infarction (AMI) is a severe cardiovascular disease with complex pathogenesis, posing significant threats to human health. Liensinine, an alkaloid derived from lotus plumule, has shown potential cardioprotective effects in preliminary studies, but its specific molecular targets and mechanisms in MI treatment remain unclear. Differential expression genes (DEGs) associated with AMI were identified from the GSE166780 dataset. Liensinine targets were predicted via SwissTargetPrediction and CTD database. After removing duplicates, the resulting targets were intersected with the AMI DEGs. Protein-protein interactions (PPI) networks were constructed using STRING. KEGG and GO enrichment analyses were performed on Sangebox, and results were visualized in Cytoscape. Key genes were screened via CytoHubba (DMNC, MCC) and MCODE plugins, and intersected with genes selected by LASSO, SVM, and RF. Algorithms. An ischemia-reperfusion (I/R) model was established in AC16 cells. After treatment with different concentrations of liensinine, the optimal dose was determined by CCK8. Gene expression (qRT-PCR), apoptosis (flow cytometry), and levels of IL-6, IL-1β, and TNF-α (ELISA) were detected. DEGs in MI were identified from the GSE166780 dataset, with 27 genes overlapping with liensinine targets and enriched in key pathways (AGE-RAGE, TNF signaling). Network analysis and machine learning refined these to 4 core genes. In vitro validation using an AC16 I/R model showed NLRP3 was significantly upregulated following AMI; treatment with liensinine (0.5 μM) suppressed NLRP3, alleviated cell injury, and reduced pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), confirming its protective role via NLRP3 regulation. Liensinine exerted protective effects against MI by suppressing NLRP3, thereby mitigating cell injury and inflammation.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 10","pages":"100190-100190"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147899441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on the mechanism by which quercetin affects ferroptosis in breast cancer cells through regulating USP9X/PIAS4","authors":"Zitong Fu, Bo Wei, Yanming Huang, Lingbing Yang, Wantong Sun","doi":"10.1016/j.lddd.2025.100169","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100169","url":null,"abstract":"Breast cancer stands as a formidable malignant tumor posing a severe threat to women’s health globally, characterized by alarmingly high rates of morbidity and mortality. Quercetin has demonstrated a substantial impact in restraining the malignant behaviors exhibited by breast cancer cells. Meanwhile, it has been uncovered that both deubiquitinating enzyme ubiquitin specific peptidase 9 X-linked (USP9X) and protein inhibitor of activated STAT 4 (PIAS4) are implicated in the progression of breast cancer. Nevertheless, thus far, no pertinent research has elucidated whether there exists an inherent association among quercetin, USP9X, and PIAS4. In this study, the viability, proliferation, and apoptosis of breast cancer cells were measured by MTT, EdU, and flow cytometry. Then, Caspase 3 activity, ROS, MDA, iron and Fe 2 + levels, and mitochondrial membrane potential were evaluated with the corresponding kits. Meanwhile, the mRNA and protein levels of USP9X and PIAS4 were determined by qRT-PCR and western blot. Besides, molecular docking was applied to visualize the binding of quercetin and USP9X. The association of USP9X with PIAS4 was predicted by bioinformatics analysis. And the ubiquitination level of PIAS4 was measured by IP and IB techniques. Firstly, quercetin treatment could effectively prevent the proliferation of breast cancer cells and promote apoptosis, oxidative stress and ferroptosis. USP9X was highly expressed in breast cancer and silencing it produced similar results as quercetin treatment. Molecular docking verified that quercetin could bind to USP9X. Meanwhile, reversion assay confirmed that quercetin inhibited the malignant behavior of breast cancer cells by binding to USP9X. At this time, it was also found that PIAS4 expression was positively correlated with USP9X, and USP9X was able to mediate the deubiquitination of PIAS4, further aggravating breast cancer. This study elucidated the mechanism of action of quercetin: by binding to USP9X, it diminished USP9X-mediated deubiquitination of PIAS4, consequently blocking the proliferation of breast cancer cells and stimulating oxidative stress and ferroptosis, ultimately achieving a therapeutic effect against breast cancer.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 10","pages":"100169-100169"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147884522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanistic basis of Jiang Dan Jian Ji decoction (JDJJ) for chronic kidney disease treatment through network pharmacology","authors":"Bin Wang, Lv Jing","doi":"10.1016/j.lddd.2025.100177","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100177","url":null,"abstract":"","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 10","pages":"100177-100177"},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147893293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic mechanisms of Radix bupleuri in plasma cell mastitis: A multi-modal study combining network pharmacology, molecular docking, and dynamics simulations","authors":"Zewen Xiao, Yan Gong, Ling Zhong, Qing-Qing Fu, Dequan Xiao","doi":"10.1016/j.lddd.2025.100145","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100145","url":null,"abstract":"Radix bupleuri (Chaihu), a cornerstone botanical in traditional Chinese medicine, exerts anti-inflammatory and immunomodulatory properties. This study combined multiple methods to investigate the pharmacological mechanisms of Chaihu in treating plasma cell mastitis (PCM), a chronic inflammatory breast disorder. Active components and potential candidates of Chaihu were selected, the PCM-related regulatory molecules were screened, and their common targets were identified. Protein-protein interaction (PPI) network of shared targets and drug-compound-target-disease network were constructed. GO annotation and KEGG analysis were conducted employing DAVID. Molecular docking studies were conducted with AutoDock Vina. Conformational dynamics were assessed through normal mode calculations using iMODS. Thirteen bioactive ingredients of Chaihu, 184 candidate targets of Chaihu, and 980 putative PCM-related targets were identified. Cross-referencing the 184 Chaihu-derived targets with 980 PCM-associated targets identified 61 shared candidates. Five proteins (AKT1, TNF, IL1B, IL6, and JUN) were identified as core regulatory nodes. Quercetin (MOL000098) emerged as the most influential component. GO annotation revealed that these shared candidates were involved in inflammatory response, apoptotic process, cell migration regulation. KEGG pathway results linked the effects of Chaihu on estrogen-mediated signaling, PI3K-Akt, and MAPK pathways. Molecular docking studies demonstrated the strong binding capacity of quercetin with AKT1, TNF, and IL1B. Conformational dynamics showed that all quercetin-protein complexes exhibited distinct dynamic properties, with the IL1B-quercetin interaction as the most stable system. Our study shows that Chaihu exhibits therapeutic potential in PCM via the modulation of diverse molecular targets and signaling pathways.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 9","pages":"100145-100145"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147913942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin ameliorates the progression of osteoarthritis through the METTL3/OLFM4 pathway","authors":"Lijun Yu, Gang Yu, Huajie Wu, Bangshun Zhu, Hao Yin, Wuhan Wang","doi":"10.1016/j.lddd.2025.100148","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100148","url":null,"abstract":"Previous studies have indicated that curcumin (Cur) exhibits excellent anti-inflammatory and anti-oxidant properties and possesses potential therapeutic value in Osteoarthritis (OA). However, the underlying mechanism of Cur in OA is still unclear. Interleukin-1β (IL-1β) was used to induce an OA chondrocyte model. Cell viability, proliferation, and apoptosis were determined using Cell Counting Kit-8, 5-ethynyl-2’-deoxyuridine, and flow cytometry. ELISA assessed IL-6 and TNF-α levels. Special assay kits examined Reactive oxygen species and malondialdehyde levels. Western blot detected Olfactomedin 4 (OLFM4), Methyltransferase-like 3 (METTL3), and insulin-like growth factor-2 mRNA-binding proteins 2 (IGF2BP2) protein levels. Interaction between METTL3 and OLFM4 was verified using MeRIP and RIP assays. Besides, we established a sodium monoiodoacetate-induced rat knee OA model to validate the effect of Cur against OA. Cur treatment repressed IL-1β-caused CHON-001 cell apoptosis, inflammation response, and oxidative stress. OLFM4 or METTL3 upregulation could abolish the inhibitory role of Cur on IL-1β-induced CHON-001 cell injury. METTL3 increased the stability of OLFM4 mRNA via m6A methylation, and the m6A reader IGF2BP2 was verified to participate in the regulation of OLFM4. In addition, Cur attenuated OA pathology in rat knee joints. Cur treatment could protect chondrocytes from IL-1β-caused injury by regulating METTL3-mediated m6A modification of OLFM4 mRNA, which provides a possible therapeutic agent for OA.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 9","pages":"100148-100148"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147917929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation into the mechanism of columbianadin’s inhibition of breast cancer development using network pharmacology and molecular dynamics simulation","authors":"Jiejie Hu, Siyuan Liu, Chengdong Qin, Lihong Hu, Yang Yu","doi":"10.1016/j.lddd.2025.100129","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100129","url":null,"abstract":"Breast cancer (BC) remains a significant global health challenge, necessitating the exploration of novel therapeutic agents. Columbianadin (CBN), a natural compound, has shown potential anti-cancer properties. This study employed network pharmacology to elucidate the molecular mechanisms underlying CBN’s regulation of BC, particularly focusing on its effects on cell proliferation, apoptosis, migration, invasion, and ferroptosis. The study utilized 5-Ethynyl-2’-deoxyuridine assay to analyze cell proliferation and flow cytometry for apoptosis and reactive oxygen species (ROS) levels. Transwell assays were used to analyze cell migration and invasion. Colorimetric assays were performed to measure malondialdehyde, glutathione, and Fe 2 + levels. Western blotting assay was used to assess protein expression. Target genes of CBN were predicted using the SwissTargetPrediction platform, and BC-related genes were identified from the GeneCards database. Overlapping genes were used to construct a protein-protein interaction network, followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Molecular docking, dynamics simulation, and cellular thermal shift assays were conducted to identify bindings of CBN with AKT serine/threonine kinase 1 (AKT1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), prostaglandin-endoperoxide synthase 2 (PTGS2), and SRC proto-oncogene, non-receptor tyrosine kinase (SRC). A xenograft mouse model assay was performed to analyze the effect of CBN on tumor formation in vivo . CBN treatment significantly inhibited the proliferation, migration, and invasion of SKBR3 cells, while inducing apoptosis and ferroptosis. Moreover, CBN treatment inhibited tumor formation in vivo . Thirty-eight overlapping genes were identified between the SwissTargetPrediction and GeneCards databases. The top four target proteins of CBN in BC treatment included AKT1, PIK3CA, PTGS2, and SRC. KEGG pathway analysis linked these genes to the PI3K-Akt pathway, EGFR tyrosine kinase inhibitor resistance, PD-L1 expression, PD-1 checkpoint pathway in cancer, and VEGF signaling pathway. GO analysis revealed their involvement in signal transduction, protein autophosphorylation, and receptor signaling pathways, along with diverse kinase activities. Molecular docking and dynamics simulation confirmed strong bindings of CBN with the four identified target proteins, and CBN treatment reduced their protein expression and enhanced their thermal stability in SKBR3 cells. Further, CBN treatment reduced the p-PI3K/PI3K and p-AKT/AKT ratios in SKBR3 cells. CBN effectively inhibited the proliferation, migration, and invasion of SKBR3 cells, while inducing apoptosis and ferroptosis, primarily by downregulating AKT1, PIK3CA, PTGS2, and SRC. These findings highlight CBN’s potential as a therapeutic agent for BC. • CBN treatment inhibited the proliferation, migration and invasion of SKBR3 cells. • CBN treatment induced","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 8","pages":"100129-100129"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147910890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14-induced N6-methyladenosine modification on TPX2 mRNA inhibits tumor progression in clear cell renal cell carcinoma","authors":"Mingqiang Su, Wei Chen, Jingxian Luo, Xianyong Li, Dayong Ye, DengJun Han, Guangqing Fu","doi":"10.1016/j.lddd.2025.100138","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100138","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) accounts for 70 % of all renal cell carcinoma (RCC) types, and 30 % of patients with ccRCC present with metastasis at the time of initial diagnosis. Given the high prevalence of metastasis, basic research into potential therapeutic targets for unresectable and metastatic ccRCC is crucial. Our study aims to explore the regulatory mechanism of targeting protein for Xklp2 (TPX2) in ccRCC, which may provide novel insights for the treatment of this disease. Reverse-transcription polymerase chain reaction (RT-qPCR) was performed to analyze mRNA expression, whereas Western blot (WB) was used to detect protein expression. The abilities of colony formation and proliferation, as well as the proportion of apoptosis in treated RCC cells, were assessed using colony formation, 5-Ethynyl-2′-deoxyuridine (EdU), and flow cytometry assays, respectively. The intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and ferrous ion (Fe 2+ ) in treated RCC cells were examined by corresponding kits. A tumor cell-derived xenograft model was utilized to verify the regulatory function of TPX2 in vivo . The RBPsuite website and methylated RNA immunoprecipitation (MeRIP)-qPCR assay were employed to verify the N6-methyladenosine (m 6 A) modification level on TPX2 mRNA, mediated by methyltransferase-like 14 (METTL14). The stability of TPX2 mRNA triggered by METTL14 was evaluated by RNA decay assay. The expression of TPX2 was elevated in ccRCC tissues and cell lines. TPX2 knockdown in RCC cells inhibited the abilities of cell colony formation and proliferation and boosted cell apoptosis, and its knockdown facilitated cell ferroptosis by hindering the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The tumor cell-derived xenograft tumor model exhibited that TPX2 silence inhibited tumor growth in vivo . RCC cells with METTL14 overexpression showed higher levels of m 6 A-modifying sites compared to those without overexpression. METTL14 overexpression in RCC cells boosted TPX2 mRNA degradation and impeded its protein expression in a YTHDF2-dependent manner. In addition, RCC cells overexpressing METTL14 displayed impaired abilities for colony formation and proliferation, as well as an increased proportion of apoptotic cells. However, these effects were mitigated by the overexpression of TPX2. TPX2 overexpression also reversed the promotion of ferroptosis induced by METTL14 upregulation. METTL14-mediated m 6 A modification on TPX2 mRNA inhibited tumor progression by repressing the expression of SLC7A11 and GPX4 in ccRCC.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 8","pages":"100138-100138"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147907759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing the neuroprotective mechanism of irisin on stroke based on network pharmacology, molecular docking and experimental validation","authors":"Yanyan Huang, Yueyi Zhang, Miaoduan Li, Ting Tang, Jinhuan Ning, Mingni Yang, Zetuo Wang","doi":"10.1016/j.lddd.2025.100133","DOIUrl":"https://doi.org/10.1016/j.lddd.2025.100133","url":null,"abstract":"Irisin has been confirmed to play a neuroprotective effect in stroke. However, the mechanism of irisin in treating stroke remains unclear. Irisin targets were screened by SwissTargetPrediction and superpred database, and stroke-related targets were downloaded from GeneCards website and OMIM database. The intersection targets between irisin and stroke was obtained by Venn diagram. Then, the intersection targets were imported into the STRING database to construct protein-protein interaction network. DAVID database was used to perform GO and KEGG pathway enrichment analysis, and Cytoscape3.9.0 software was performed to construct the drug-disease-target model. AutoDockTools 1.5.7 and PYMOL software were used to analyze the molecular docking results of irisin and hub targets, and molecular dynamics simulation was analyzed using IMDS software. Human neuroblastoma cells (SK-N-SH) were induced with oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic stroke cell model. Cell viability, apoptosis and inflammation were analyzed using CCK8 assay, flow cytometry and ELISA. The expression of 8 hub targets was detected by qRT-PCR. A total of 100 irisin targets and 8376 stroke targets were screened, and 85 intersection targets were obtained. Enrichment analyses revealed that nitrogen metabolism, cAMP signal pathway, adipocytokine signaling pathway and HIF-1 signaling pathway were significantly enriched by multi-targets. Drug-disease-target model was constructed and the 8 hub genes were screened, including TNF, HIF1A, TLR4, HSP90AB1, NFKB1, NFE2L2, IL2 and KEAP1. Molecular docking and dynamics simulation revealed that 8 hub genes (TNF, HIF1A, TLR4, HSP90AB1, NFKB1, NFE2L2, IL2 and KEAP1) exhibited more prominent binding energy with irisin. Irisin could inhibit OGD/R-induced SK-N-SH cell apoptosis and inflammation via regulating the expression of 8 hub targets. Irisin may alleviate stroke process by regulating TNF, HIF1A, TLR4, HSP90AB1, NFKB1, NFE2L2, IL2 and KEAP1, which constructed a pharmacological network to clarify the mechanisms of irisin in treating stroke.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"22 8","pages":"100133-100133"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147922444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}