Acta Pharmacologica Sinica最新文献

{"title":"Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction.","authors":"Rui Ni, Xiao-Yun Ji, Ting Cao, Xiu-Wen Liu, Chao Wang, Chao Lu, Angel Peng, Zhu-Xu Zhang, Guo-Chang Fan, Jin Zhang, Zhao-Liang Su, Tian-Qing Peng","doi":"10.1038/s41401-024-01424-3","DOIUrl":"10.1038/s41401-024-01424-3","url":null,"abstract":"<p><p>Myocardial dysfunction is a decisive factor of death in septic patients. Cyclophilin F (PPIF) is a major component of the mitochondrial permeability transition pore (mPTP) and acts as a critical mPTP sensitizer triggering mPTP opening. In sepsis, decreased NAD⁺ impairs Sirtuin 3 function, which may prevent PPIF de-acetylation. Repletion of NAD⁺ with nicotinamide mononucleotide (NMN) reduces myocardial dysfunction in septic mice. In addition, administration of the mPTP inhibitor cyclosporine-A attenuated sepsis-induced myocardial dysfunction, and deletion of PPIF reduced lung and liver injuries in sepsis, leading to increased survival. It is plausible that NAD⁺ repletion with NMN may prevent mPTP opening in protecting septic hearts through PPIF de-acetylation and/or inhibition of mitochondrial ROS-mediated PPIF oxidation. In this study we investigated how NMN alleviated myocardial dysfunction in septic mice. Sepsis was induced in mice by injection of LPS (4 mg/kg, i.p.). Then mice received NMN (500 mg/kg, i.p.) or mito-TEMPO (0.7 mg/kg, i.p.) right after LPS injection, and subjected to echocardiography for assessing myocardial function. At the end of experiment, the heart tissues and sera were collected for analyses. In vitro experiments were conducted in neonatal mouse cardiomyocytes treated with LPS (1 µg/mL) in the presence of NMN (500 µmol/L) or mito-TEMPO (25 nmol/L). We showed that LPS treatment markedly increased mitochondrial ROS production and induced lysosomal dysfunction and aberrant autophagy in cardiomyocytes and mouse hearts, leading to inflammatory responses and myocardial injury and dysfunction in septic mice. NMN administration attenuated LPS-induced deteriorative effects. Selective inhibition of mitochondrial superoxide production with mito-TEMPO attenuated lysosomal dysfunction and aberrant autophagy in septic mouse hearts. Notably, LPS treatment significantly increased acetylation and oxidation of PPIF, which was prevented by NMN in mouse hearts. Knockdown of PPIF replicated the beneficial effects of NMN or mito-TEMPO on ROS production, lysosomal dysfunction, aberrant autophagy, and myocardial injury/dysfunction in sepsis. In addition, administration of NMN abrogated LPS-induced ATP5A1 acetylation and increased ATP5A1 protein levels and ATP production in septic mouse hearts. This study demonstrates that NMN modulates the interplay of mitochondrial ROS and PPIF in maintaining normal lysosomal function and autophagy and protecting ATP5A1 and ATP production during sepsis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"976-988"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNX3 mediates heart failure by interacting with HMGB1 and subsequently facilitating its nuclear-cytoplasmic translocation.","authors":"Hong Li, Ming-Xia Peng, Rui-Xue Yang, Jian-Xing Chen, Yue-Mei Wang, Pan-Xia Wang, Yue-Huai Hu, Di-Yi Pan, Pei-Qing Liu, Jing Lu","doi":"10.1038/s41401-024-01436-z","DOIUrl":"10.1038/s41401-024-01436-z","url":null,"abstract":"<p><p>Sorting nexins (SNXs) as the key regulators of sorting cargo proteins are involved in diverse diseases. SNXs can form the specific reverse vesicle transport complex (SNXs-retromer) with vacuolar protein sortings (VPSs) to sort and modulate recovery and degradation of cargo proteins. Our previous study has shown that SNX3-retromer promotes both STAT3 activation and nuclear translocation in cardiomyocytes, suggesting that SNX3 might be a critical regulator in the heart. In this study we investigated the role of SNX3 in the development of pathological cardiac hypertrophy and heart failure. We generated abdominal aortic constriction (AAC) rat model and transverse aortic constriction (TAC) mouse model; hypertrophic neonatal rat cardiomyocytes (NRCMs) were induced by exposure to isoproterenol (10 μM). We showed that the expression of SNX3 was significantly upregulated in ISO-treated NRCMs and in the failing heart of AAC rats. Overexpression of SNX3 by intramyocardial injection of Ad-SNX3 induced heart failure in rats, and increased the susceptibility of NRCMs to ISO-induced myocardial injury in vitro. In contrast, conditional knockout of SNX3 in cardiac tissue in mice rescued the detrimental heart function in TAC mice, and knockdown of SNX3 protected against ISO-induced injury in NRCMs and AAC rats. We then conducted immunoprecipitation-based mass spectrometry and localized surface plasmon resonance, and demonstrated a direct interaction between SNX3-retromer and high mobility group box 1 (HMGB1), which mediated the efflux of nuclear HMGB1. Moreover, overexpression of HMGB1 in NRCMs inhibited the pro-hypertrophic effects of SNX3, whereas knockdown of HMGB1 abolished the protective effect of SNX3-deficiency. These results suggest that HMGB1 might be a direct cargo protein of SNX3-retromer, and its interaction with SNX3 promotes its efflux from the nucleus, leading to the pathological development of heart failure.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"964-975"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial FOSL1 drives angiotensin II-induced myocardial injury via AT1R-upregulated MYH9.","authors":"Wen-Jing Zhao, Yi Qian, Yi-Feng Zhang, Ai-Hua Yang, Jia-Xin Cao, Hong-Yan Qian, Yi Liu, Wei-Zhong Zhu","doi":"10.1038/s41401-024-01410-9","DOIUrl":"10.1038/s41401-024-01410-9","url":null,"abstract":"<p><p>Vascular remodeling represents a pathological basis for myocardial pathologies, including myocardial hypertrophy and myocardial infarction, which can ultimately lead to heart failure. The molecular mechanism of angiotensin II (Ang II)-induced vascular remodeling following myocardial infarction reperfusion is complex and not yet fully understood. In this study, we examined the effect of Ang II infusion on cardiac vascular remodeling in mice. Single-cell sequencing showed Ang II induced cytoskeletal pathway enrichment and that FOS like-1 (FOSL1) affected mouse cardiac endothelial dysfunction by pseudotime analysis. Myosin heavy chain 9 (MYH9) was predominantly expressed in primary cardiac endothelial cells. The Ang II type I receptor blocker telmisartan and the protein kinase C inhibitor staurosporine suppressed Ang II-induced upregulation of MYH9 and FOSL1 phosphorylation in human umbilical vein endothelial cells. Silencing MYH9 abolished Ang II-mediated inhibition of angiogenesis in human umbilical vein endothelial cells, and attenuated AngII-induced vascular hyperpermeability. We found that FOSL1 directly bound to the MYH9 promoter and thus activated transcription of MYH9 by the dual luciferase reporter and chromatin immunoprecipitation assays, leading to vascular dysfunction. In vivo, 6 weeks after injecting adeno-associated virus-ENT carrying the TEK tyrosine kinase (tie) promoter-driven short hairpin RNA for silencing FOSL1 (AAV-tie-shFOSL1), cardiac function represented by the ejection fraction and fractional shortening was improved, myocardial fibrosis was decreased, protein levels of phosphorylated FOSL1, MYH9, and collagen type I alpha were reduced, and cardiac vascular density was recovered in mice with endothelial Fosl1-specific knockdown in Ang II-infused mice. In ischemia-reperfusion mice, AAV-shFosl1 mice had a reduced infarct size and preserved cardiac function compared with control AAV mice. Our findings suggest a critical role of the FOSL1/MYH9 axis in hindering Ang II-induced vascular remodeling, and we identified FOSL1 as a potential therapeutic target in endothelial cell injuries induced by myocardial ischemia-reperfusion.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"922-939"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colchicine reduces neointima formation and VSMC phenotype transition by modulating SRF-MYOCD activation and autophagy.","authors":"Bu-Chun Zhang, Wen-Ya Zhu, Sheng-Nan Wang, Meng-Meng Zhu, Hui Ma, Liang Dong, Xiao-Xiao Yang, Chuan-Rui Ma, Li-Kun Ma, Yuan-Li Chen","doi":"10.1038/s41401-024-01438-x","DOIUrl":"10.1038/s41401-024-01438-x","url":null,"abstract":"<p><p>Vascular smooth muscle cell (VSMC) phenotype transformation significantly contributes to vascular intimal hyperplasia. However, effective preventive and therapeutic measures are lacking. Colchicine, a binary alkaloid derived from Colchicum autumnale, is traditionally used for treating inflammatory diseases. Its role in neointima formation is not fully understood. Here, we investigated the role of colchicine in vascular intimal hyperplasia. We found that colchicine significantly reduced vascular intimal hyperplasia in an animal model at 7, 14, and 28 days post carotid artery ligation and increased the number of contractile-phenotype VSMCs (SMA-positive cells) in the neointimal areas. In vitro experiments demonstrated that colchicine facilitated the transition of VSMCs from a proliferative phenotype to a contractile phenotype. Additionally, colchicine attenuated PDGF-BB-induced phenotypic conversion and upregulated the expression of serum response factor (SRF) and myocardin (MYOCD). Further molecular mechanistic studies revealed that colchicine inhibited the expression of forkhead box protein O3A (FOXO3A) to increase the activation of the SRF‒MYOCD complex. FOXO3A can bind to MSX1/2, thereby inhibiting the expression of SRF-MYOCD and contractile genes. Moreover, colchicine maintains vascular homeostasis and stabilizes the contractile phenotype by affecting the expression of autophagy-related genes (LC3II, p62, and Beclin-1) induced by FOXO3A. Additionally, colchicine inhibited monocyte/macrophage infiltration and inflammatory cytokine expression. In summary, this study suggests that colchicine inhibits vascular intimal hyperplasia by modulating FOXO3A-mediated SRF-MYOCD activation and autophagy, providing new insights for future therapeutic approaches targeting occlusive vascular diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"951-963"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis.","authors":"Yue-Kang Li, Fu-Jing Ge, Xiang-Ning Liu, Chen-Ming Zeng, Mei-Jia Qian, Yong-Hao Li, Ming-Ming Zheng, Jing-Jing Qu, Liang-Jie Fang, Jin-Jian Lu, Bo Yang, Qiao-Jun He, Jian-Ya Zhou, Hong Zhu","doi":"10.1038/s41401-024-01427-0","DOIUrl":"10.1038/s41401-024-01427-0","url":null,"abstract":"<p><p>Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1045-1057"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acid-sensing ion channel 1a promotes alcohol-associated liver disease in mice via regulating endoplasmic reticulum autophagy.","authors":"Yue-Qin Zhu, Li-Li Wang, Zi-Hao Li, Shi-Shun Qian, Zhou Xu, Jin Zhang, Yong-Hu Song, Xue-Sheng Pan, Na Du, Amira Abou-Elnour, Lynn Jia Tay, Jing-Rong Zhang, Meng-Xue Li, Yu-Xian Shen, Yan Huang","doi":"10.1038/s41401-024-01423-4","DOIUrl":"10.1038/s41401-024-01423-4","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is a hepatocyte dysfunction disease caused by chronic or excessive alcohol consumption, which can lead to extensive hepatocyte necrosis and even liver failure. Currently, the pathogenesis of ALD and the anti-ALD mechanisms have not been fully elucidated yet. In this study, we investigated the effects of endoplasmic reticulum autophagy (ER-phagy) in ALD and the role of acid-sensing ion channel 1a (ASIC1a) in ER stress-mediated ER-phagy. A mouse model of ALD was established using the Gao-Binge method and the AML12 cell line treated with alcohol was used as an in vitro model. We showed that ASIC1a expression was significantly increased and ER-phagy was activated in both the in vivo and in vitro models. In alcohol-treated AML12 cells, we showed that blockade of ASIC1a with PcTx-1 or knockdown of ASIC1a reduced alcohol-induced intracellular Ca²⁺ accumulation and ER stress. In addition, inhibition of ER stress with 4-PBA reduced the level of ER-phagy. Furthermore, knockdown of the ER-phagy receptor family with sequence similarity 134 member B (FAM134B) alleviated alcohol-triggered hepatocyte injury and apoptosis. In conclusion, this study demonstrates that alcohol activates ER stress-induced ER-phagy and liver injury by increasing ASIC1a expression and ASIC1a-mediated Ca²⁺ influx, providing a novel strategy for the treatment of ALD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"989-1001"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRADD-mediated pyroptosis contributes to diabetic cardiomyopathy.","authors":"Yang-Yang Zheng, Dan-Ning Shen, Xiao-Lu Peng, Wen-Qing San, Qian-You Zhou, Sheng-Ju Yang, Guo-Liang Meng, Jia-Hai Shi, Yun Chen","doi":"10.1038/s41401-024-01450-1","DOIUrl":"10.1038/s41401-024-01450-1","url":null,"abstract":"<p><p>Regulated cell death like pyroptosis is one vital cause of diabetic cardiomyopathy (DCM), which eventually leads to heart failure. Tumor necrosis factor (TNF) receptor-associated death domain protein (TRADD) is an adapter protein with multiple functions that participates in the pathophysiological progress of different cardiovascular disorders via regulating regulated cell death. Studies have shown that TRADD combines with receptor-interacting protein kinase 3 (RIPK3) and facilitates its activation, thereby mediating TNF-induced necroptosis. However, no direct relationship between TRADD and pyroptosis has been identified. In this study, we investigated the role and mechanisms of TRADD in pyroptosis during DCM. We established a streptozotocin (STZ)-induced diabetic mouse model and high glucose (HG)-treated cardiomyocytes model. We showed that the expression levels of TRADD were significantly increased in the hearts of diabetic mice and HG-treated cardiomyocytes. Knockdown of TRADD did not affect blood glucose and triglyceride levels, but significantly improved cardiac function, and attenuated myocardial hypertrophy, fibrosis, and pyroptosis in the heart of diabetic mice. Furthermore, both knockdown of TRADD and application of TRADD inhibitor apostatin-1 (Apt-1, 10 μM) significantly ameliorated cell injury and pyroptosis in HG-treated cardiomyocytes. We demonstrated that HG treatment increased the expression of X-box binding protein 1 (XBP1) and enhanced the binding of XBP1 to the TRADD promoter to elevate TRADD expression in the cardiomyocytes. Collectively, this study provides evidence that TRADD-mediated pyroptosis contributes to DCM, suggesting that strategies to inhibit TRADD activity may be a novel approach for DCM treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"940-950"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SP600125, a selective JNK inhibitor, is a potent inhibitor of NAD(P)H: quinone oxidoreductase 1 (NQO1).","authors":"Bing-Ling Zhong, Yi-Fei Zhang, Hao-Yi Zheng, Qiang Chen, Hua-Dong Lu, Xiu-Ping Chen","doi":"10.1038/s41401-024-01418-1","DOIUrl":"10.1038/s41401-024-01418-1","url":null,"abstract":"<p><p>The c-Jun N-terminal kinases (JNKs) has been identified as a critical modulator in multiple cellular processes, including stress stimulus, inflammation, cell proliferation, apoptosis, etc. SP600125 is a widely used ATP-competitive reversible JNKs inhibitor. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoprotein mediated two or four electron-reduction of quinones. Here, we showed that SP600125 bind to the active pocket of NQO1 and inhibit NQO1 activity. SP600125 exhibits comparable inhibitory effects on NQO1-mediated quinone bioactivation, H₂O₂ generation, and cell death, as the specific NQO1 inhibitor dicoumarol (DIC). Importantly, the inhibitory effects of SP600125 on NQO1 are independent of JNKs inhibition. These results suggested that SP600125 is a novel NQO1 inhibitor, which provides new insights into the mechanism of action of SP600125. Furthermore, SP600125 should be used more cautiously as a JNKs inhibitor, especially when NQO1 is highly expressed. SP600125 competed with β-Lap (NQO1-bioactivated drugs) for binding to NQO1, and inhibited NQO1-dependent cell death.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1137-1144"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STT3-mediated aberrant N-glycosylation of CD24 inhibits paclitaxel sensitivity in triple-negative breast cancer.","authors":"Jun Wang, Hui-Min Zhang, Guan-Hua Zhu, Li-Li Zhao, Ji Shi, Zhou-Tong Dai, Jia-Peng Li, Xing-Rui Li, Fan Sun, Yuan Wu, Shao-Yong Chen, Han-Ning Li, Xing-Hua Liao, Yuan Xiang","doi":"10.1038/s41401-024-01419-0","DOIUrl":"10.1038/s41401-024-01419-0","url":null,"abstract":"<p><p>Paclitaxel is one of the main chemotherapic medicines against triple-negative breast cancer (TNBC) in clinic. However, it has been perplexed by paclitaxel resistance in TNBC patients, resulting in a poor prognosis. Abnormal protein glycosylation is closely related to the occurrence and progression of tumors and malignant phenotypes such as chemotherapy resistance. CD24 is a highly glycosylated membrane protein that is highly expressed in TNBC, leading to tumorigenesis and poor prognosis. In this study we investigated the relationship between abnormal glycosylation of CD24 and paclitaxel susceptibility in TNBC and the molecular mechanisms. We showed that CD24 protein levels were significantly up-regulated in both TNBC tissues and cells, and CD24 protein was highly glycosylated. Genetic and pharmacological inhibition of N-glycosylation of CD24 enhances the anticancer activity of paclitaxel in vitro and tumor xenograft models. We revealed that the molecular mechanism of N-glycosylation of CD24 in paclitaxel resistance involved inhibition of ferroptosis, a new form that regulates cell death. Inhibition of N-glycosylation of CD24 increased glutathione consumption, iron content, and lipid peroxidation, resulting in paclitaxel-induced ferroptosis. We demonstrated that endoplasmic reticulum (ER)-associated glycosyltransferase STT3 isoforms (including both STT3A and STT3B isoforms) enable N-glycosylation of the L-asparagine (N) site. Knockout of the endogenous STT3 isoform in TNBC cells partially reduced the glycosylation status of CD24. Our results demonstrate the critical role of N-glycosylation of CD24 in weakening drug sensitivity by inhibiting ferroptosis, highlighting new insights that targeting N-glycosylation of CD24 has great potential to promote chemotherapy sensitivity and efficacy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1097-1110"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel dual-target inhibitors of LSD1/EGFR for non-small cell lung cancer therapy.","authors":"Yu Wei, Ming-Ming Sun, Rui-Li Zhang, Lin Wang, Li-Hong Yang, Chang-Liang Shan, Jian-Ping Lin","doi":"10.1038/s41401-024-01439-w","DOIUrl":"10.1038/s41401-024-01439-w","url":null,"abstract":"<p><p>Histone lysine-specific demethylase 1 (LSD1) is overexpressed in various solid and hematological tumors, suggesting its potential as a therapeutic target, but there are currently no LSD1 inhibitors available on the market. In this study we employed a computer-guided approach to identify novel LSD1/EGFR dual inhibitors as a potential therapeutic agent for non-small cell lung cancer. Through a multi-stage virtual screening approach, we found L-1 and L-6, two compounds with unique scaffolds that effectively inhibit LSD1 with IC₅₀ values of 6.24 and 9.26 μM, respectively. Using molecular similarity-based screening, 48 analogs of L-1 and L-6 were retrieved from ChemDiv library, 18 analogs were selected for biological activity analysis. Eight compounds showed weaker inhibitory activity against LSD1, with IC₅₀ values of 19.79 - 35.70 μM. Moreover, L-1, L-6, and two analogs of L-6 (D-14 and D-16) were found to inhibit triple-mutant EGFR (L858R/T790M/C797S) with potencies ranging from 5.01 to 86.70 μM, and to inhibit double-mutant EGFR (T790M/L858R) with potencies ranging from 2.06 to 64.36 μM. In BaF3 cells that stably express EGFR (L858R/T790M/C797S), the inhibitory activity of L-1, L-6, D-14 and D-16 ranged from 2.72 to 8.99 μM. L-1 that shows the highest biological activity across BaF3 cell, mutant EGFR kinase and LSD1 assays due to its dual targeting of LSD1/EGFR, emerges as a promising lead compound for non-small cell lung cancer treatment. This study demonstrates that L-1 efficiently inhibits lung cancer growth in vitro and in vivo, suggesting it as a potential lead for non-small cell lung cancer treatment, highlighting the utility of virtual screening methods in discovering multi-target inhibitors and strategies for other diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1030-1044"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}