Acta Pharmacologica Sinica最新文献

{"title":"Modeling exposure-driven adverse events of EGFR TKIs in the treatment of patients with non-small cell lung cancer.","authors":"Ling Yong, Yan'e Liu, Wei-Zhe Jian, Lei Cai, Tian-Yu Bao, Chen Liu, En-Ze Gan, Tian-Yu Wang, Ping-Yao Luo, Bao-Shan Cao, Wei Liu, Tian-Yan Zhou","doi":"10.1038/s41401-025-01573-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01573-z","url":null,"abstract":"<p><p>The adverse events associated with antitumour drugs have recently emerged as an increasingly significant clinical concern. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) serve as pivotal therapeutic agents for non-small cell lung cancer (NSCLC). However, considerable interindividual variability exists in drug exposure, along with a high incidence and severity of adverse events. In this study, we quantitatively investigated the impacts of EGFR TKI exposure and other covariates on the severity of the maximum grade of drug-related adverse events (MDRAE) in NSCLC patients treated with EGFR TKIs. Data were collected from 277 patients treated with gefitinib, icotinib, afatinib or osimertinib. Population pharmacokinetic (PopPK) models were constructed for each drug, and individual exposure metrics were derived through model simulations. Normalized individual exposures to different EGFR TKIs based on their IC₅₀ values and MDRAE data were integrated to develop an ordinal logistic regression model for an exposure-safety analysis. A user-friendly nomogram was subsequently designed. The probability of high-grade MDRAE was significantly associated with normalized exposure levels, a history of EGFR TKI treatment, sex and other factors. Model simulations revealed substantial interindividual variability in drug exposure and the probability of different grades of MDRAE for the same treatment regimen. This study quantitatively elucidates the influences of drug exposure and other critical factors on safety, thereby contributing to the formulation of individualized treatment strategies to prevent and promptly address drug safety-related issues.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contrastive learning-based drug screening model for GluN1/GluN3A inhibitors.","authors":"Kun Li, Yue Zeng, Yi-da Xiong, Hao-Chen Wu, Sui Fang, Zhi-Yan Qu, Yan Zhu, Bo Du, Zhao-Bing Gao, Wen-Bin Hu","doi":"10.1038/s41401-025-01580-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01580-0","url":null,"abstract":"<p><p>GluN3A-containing NMDA receptors have recently emerged as promising therapeutic targets for neurological disorders. However, discovering potent modulators remains a significant challenge, primarily due to the limitations of traditional high-throughput screening methods. In this study, we introduce a novel drug-target affinity prediction method, CLG-DTA, designed to enhance drug discovery for the GluN1/GluN3A receptor. This graph contrastive learning-based method incorporates natural language supervision by transforming regression labels into textual representation, and integrating them with traditional affinity data to enhance molecular representation. Additionally, a numerical knowledge graph is employed to refine continuous text embeddings, enabling precise modeling of complex drug-target interactions across diverse data modalities. Using CLG-DTA, we screened a library of 18 million compounds and identified 12 candidates for experimental validation. Among them, five compounds exhibited significant activity, with Boeravinone E demonstrating the highest potency ( <math> <msub><mrow><mi>IC</mi></mrow> <mrow><mn>50</mn></mrow> </msub> </math>  = 3.40 <math><mo>±</mo></math> 0.91 μM). These findings highlight the potential of CLG-DTA in accelerating the identification of promising GluN1/GluN3A modulators and lay a robust foundation for future therapeutic development.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The conformational epitope of a gp41-specific mucosal protective IgA binds to the HIV-1 envelope and neutralizes infection.","authors":"Inès Sahnoune, Andréa Cottignies-Calamarte, Annouk Dauvilliers, Kingsley Essemiah, Tahar Bouceba, Christophe Piesse, Daniela Tudor, Morgane Bomsel","doi":"10.1038/s41401-025-01535-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01535-5","url":null,"abstract":"<p><p>HIV-1 envelope conformational changes necessary for viral infection make the gp41 subunit a key target for antiviral drugs. Using reverse vaccinology applied to a mucosal HIV-1 neutralizing IgA, we identified P7, a 12 amino-acid peptide at the interface of the N and C-helices of gp41. We now show that P7 interacts with the trimeric HIV-1 envelope cross-clade with a nanomolar affinity, captures gp41 in a 6-Helix Bundle conformation, and binds to infected cells and free virus. Functionally, P7 neutralizes HIV infection cross-clade and inhibits cell-to-cell viral transfer. Adding a lipid tail to P7 (Lipo-P7) improved neutralization of primary CD4⁺ T cells by Transmitted / Founder clade B and primary clades A and C viruses. Lipo-P7 also neutralized a T20-resistant virus harboring gp41 G36D, V38M mutations. Altogether, P7 appears as a promising cross-clade HIV-1 antiviral peptide that could also induce protective mucosal IgA levels to prevent sexual HIV infection.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NPB-1575 attenuates neuroinflammation and resists ferroptosis in rat ischemic stroke via IRS2 signaling pathway.","authors":"Xin-Nan Li, Nian-Ying Shang, Meng-Yao Liu, Song-Yang Sui, Jing-Shu Tang, Jia-Qi Lan, Yu-Ying Kang, Bao-Dan Zhang, Zi-Peng Wen, Xin-Hong Feng, Lei Wu, Jun-Gui Dai, Ying Peng","doi":"10.1038/s41401-025-01590-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01590-y","url":null,"abstract":"<p><p>Ischemic stroke is one of the most common forms of stroke. There are no effective pharmacological agents to promote recovery yet. Dendrobium is a valuable herb in traditional Chinese medicine, which has shown antiviral, anti-inflammatory, antioxidant and immunomodulatory activities. We previously used dendrobium to synthesize a novel bibenzyl compound NPB-1575 with the ability to scavenge free radicals in vitro. Increasing evidence shows that IRS2 has biological functions other than participating in the insulin signaling pathway. In this study we utilized NPB-1575 to explore the role of IRS2 in neuroinflammation and ferroptosis during cerebral ischemia. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. NPB-1575 (25 mg/kg) was orally administered to the rats 5 min to 4 h after the surgery. We showed that NPB-1575 administration significantly reduced the infarct volume and improved neurological outcome at different stages of ischemic stroke in pMCAO rats. In the brain tissue of pMCAO rats and LPS-stimulated BV2 cells, we demonstrated that NPB-1575 exerted the anti-inflammatory effect on microglia through upregulating Nrf2 and inhibiting FOXO1 via IRS2. NPB-1575 might effectively interact with IRS2 to enhance the stability of IRS2 protein. Knockdown of IRS2 in BV2 cells reversed the protective effect of NPB-1575 against cerebral ischemic injury, manifested by upregulated NF-κB and inactivated ferroptosis defense system. In conclusion, we demonstrate that IRS2 might be a novel target in regulation of neuroinflammation and played an indispensable role in anti-ischemic injury of the brain. NPB-1575 mitigates neuroinflammation and resists ferroptosis through the IRS2/Nrf2/NF-κB axis, demonstrating its potential therapeutic effects on ischemic stroke. Cerebral ischemic injury leads to the translocation of NF-κB into the nucleus of microglia, which initiates the transcription of inflammatory genes and further releases inflammatory factors. The release of NO, IL-6, TNFα further leads to ferroptosis of neurons, which is manifested as iron overload and weakened resistance of the Xct system. NPB-1575 up-regulates IRS2, which further up-regulates pAKT/AKT and Nrf2 signaling way, down-regulates FOXO1 and NF-κB. Then the reduced microglial inflammatory response reduced neuronal ferroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An endoplasmic reticulum-targeting photodynamic AMPK agonist activates breast cancer immunotherapy through promoting immunogenic cell death and downregulation of PD-L1.","authors":"Ye-Yang Wu, Ke-Yang Zhang, Jia-Qi Huang, Jun-Mei Nie, Hong Cheng","doi":"10.1038/s41401-025-01583-x","DOIUrl":"10.1038/s41401-025-01583-x","url":null,"abstract":"<p><p>Most aggressive malignancies exhibit low immunogenicity, exacerbated by tumor immune evasion mechanisms that undermine immunotherapy efficacy. Studies indicate that AMP-activated protein kinase (AMPK) directly phosphorylates programmed cell death ligand 1 (PD-L1), promoting its degradation via the endoplasmic reticulum (ER)-associated pathway to restore and sustain cytotoxic T lymphocyte-mediated immunity. Here, we developed an ER-targeting photodynamic AMPK agonist (called PPFC) for breast cancer immunotherapy. PPFC comprised a chimeric peptide (PpIX-(PEG8-FFKDEL)₂) integrating a photosensitizer protoporphyrin IX (PpIX), a hydrophilic PEG8 linker, and the ER-targeting peptide sequence FFKDEL. The amphiphilic structure of the chimeric peptide facilitated its self-assembly into nanomicelles capable of encapsulating the AMPK agonist COH-SR4 (CS) within the chimeric peptide, forming PPFC. The findings demonstrated that this formulation enabled PPFC to accumulate in the ER of breast cancer cells, where photodynamic therapy (PDT)-generated reactive oxygen species (ROS) induced substantial ER stress, thereby amplifying immunogenic cell death (ICD) and improving tumor immunogenicity. Concurrent AMPK activation by PPFC downregulated PD-L1, counteracting immune evasion of breast cancer. The combined effects of PPFC triggered robust systemic anti-tumor immunity, eradicating primary tumors and lung metastases in 4T1 breast cancer-bearing mice. This subcellular-targeting photodynamic agonist offers a promising strategy to overcome immunosuppressive tumor microenvironments in metastatic cancers.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kv1.3 knockdown attenuates alcohol-related liver injury in mice through induction of tryptamine.","authors":"Hao Wang, Guo-Qing Xia, Ting Ke, Xi-Xi Chen, Wen-Jun Zhen, Yuan-Yuan Tian, Shi Chen, Cheng Zhang, Jun Li, Lei Zhang, De-Jun Wu, Ye-Tao Wang, Liang He, Wen-Fang Tian, Bao-Ming Wu","doi":"10.1038/s41401-025-01544-4","DOIUrl":"https://doi.org/10.1038/s41401-025-01544-4","url":null,"abstract":"<p><p>Alcohol-related liver disease (ALD) refers to a spectrum of liver diseases caused by chronic or acute excessive alcohol consumption. Excess alcohol consumption and dysregulated immunometabolism are the major contributors to the disease progression. The pathogenesis of ALD remains unclear with macrophage activity playing a key role in disease development. Kv1.3 potassium channel is essential for the regulation of macrophage function. In this study, we investigated whether Kv1.3 channels influenced the progression of ALD by modulating macrophage function. A murine model of ALD was established in male mice. We showed that Kv1.3 knockdown significantly attenuated alcohol-induced liver injury, lipid deposition, and inflammatory responses in ALD mice. Metabolomic analysis revealed that Kv1.3 knockdown significantly increased the levels of tryptamine, a tryptophan metabolite, in the liver of ALD mice. During the last 5 days of the EtOH feeding period, injection of exogenous tryptamine (1, 10, 20 mg·kg^-1·d^-1, i.p.) notably alleviated ethanol-induced liver steatosis and inflammation in ALD mice. In LPS-challenged RAW264.7 cells, tryptamine (62.5, 125, 250 μM) dose-dependently suppressed the secretion of pro-inflammatory cytokines IL-6, IL-1β and TNF-α. RNA-seq analysis of RAW264.7 cells revealed that tryptamine treatment significantly altered Toll-like receptor and NF-κB signaling pathways. We conclude that in the ALD mice, Kv1.3 negatively regulates tryptamine levels, which inhibits macrophage activation and reduces the inflammatory responses through the TLR4/NF-κB signaling pathway. Our results offer new targets and intervention strategies for the prevention and treatment of ALD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.","authors":"Bo-Rui Li, Ting Wang, Hai-Feng Hu, Di Wu, Chen-Jie Zhou, Shun-Rong Ji, Qi-Feng Zhuo, Zheng Li, Zhi-Liang Wang, Gui-Xiong Fan, De-Sheng Jing, Chong-Yuan Yu, Yi Qin, Xue-Min Chen, Jun-Feng Xu, Xiao-Wu Xu","doi":"10.1038/s41401-025-01477-y","DOIUrl":"10.1038/s41401-025-01477-y","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1742-1756"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405107","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":"Development of orthotopic mouse models for mid-low rectal cancer.","authors":"Wen Chen, Kun Shi, Dong Mo, Meng Pan, Zhong-Wu Bei, Han-Zhi Deng, Pei-Pei Yang, Qi Tong, Li-Ping Yuan, Yi-Yao Wan, Jia-Feng Liu, Li-Li Pan, Zhi-Yong Qian","doi":"10.1038/s41401-025-01489-8","DOIUrl":"10.1038/s41401-025-01489-8","url":null,"abstract":"<p><p>Mid-low rectal cancer is one of the most common types of rectal cancer and has a poor prognosis. Surgery and chemoradiotherapy are the main treatments for early and advanced rectal cancer with an overall 5-year relative survival rate of only 56.9%. Development of novel antitumor agents is needed. Animal models of disease are indispensable for drug development. The most commonly used animal models of rectal cancer are established by inducing tumors by the subcutaneous transplantation, cecum or peritoneal injection, but not injection in the rectum. Their tumor microenvironment differs from that of rectal tumors in situ, which is hard to precisely simulate the occurrence and development process and drug response of human rectal cancer. In this study, we established orthotopic mouse models of mid-low rectal cancer with primary tumors originating from the rectum, including two models that could simulate the early and advanced stages of the disease, respectively. In the first model, the local primary tumor was restricted to the rectal area of the anal verge by rectal submucosal injection, its growth could be monitored with IVIS live imaging and magnetic resonance imaging. Histological analysis confirmed that the tumor originated from the submucosal layer and then invaded the muscular layer without metastatic tumors. This model may be useful for evaluating drugs for early mid-low rectal cancer in the future. The second model featuring a rectal primary tumor accompanied with abdominal metastases was established via rectal serosal injection. In this model, a large tumor formed at the rectal injection site and then metastasized to the abdominal cavity, reproducing the process from occurrence to metastasis of mid-low rectal cancer, and may be a good tool for the evaluation of drugs for advanced-stage disease. The injection methods used in these models do not require the aid of special colonoscopes, are simple and easy to operate, and have high tumor tumorigenicity and reproducibility. These results suggest that our staged modeling can provide targeted choices for preclinical drug research of mid-low rectal cancer at different stages.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1772-1781"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405118","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":"Co-inhibition of RAGE and TLR4 sensitizes pancreatic cancer to irreversible electroporation in mice by disrupting autophagy.","authors":"Cui-Fang Ye, Jia-di Wu, Lin-Rong Li, Shu-Guo Sun, Yu-Gang Wang, Tian-An Jiang, Xin Long, Jun Zhao","doi":"10.1038/s41401-025-01487-w","DOIUrl":"10.1038/s41401-025-01487-w","url":null,"abstract":"<p><p>Irreversible electroporation (IRE) is a local ablative treatment for patients with pancreatic cancer. During the IRE procedure, high-intensity electric pulses are released intratumorally to disrupt plasma membranes and induce cell death. Since the intensity of the pulsed electric field (PEF) can be decreased by the tumor microenvironment, some cancer cells are subjected to a sublethal PEF and may survive to cause tumor recurrence later. Autophagy activation induced by anticancer therapies is known to promote treatment resistance. In this study, we investigated whether autophagy is activated in residual cancer cells after IRE and assessed the roles it plays during tumor recurrence. Subcutaneous KPC-A548 or Panc02 murine pancreatic cancer cell line xenograft mouse models were established; once the tumors reached 7 mm in one dimension, the tumor-bearing mice were subjected to IRE. For in vitro sublethal PEF treatment, the pancreatic cancer cell suspension was in direct contact with the electrodes and pulsed at room temperature. We showed that autophagy was activated in surviving residual cells, as evidenced by increased expression of LC3 and p62. Suppression of autophagy with hydroxychloroquine (60 mg/kg, daily intraperitoneal injection) markedly increased the efficacy of IRE. We demonstrated that autophagy activation can be attributed to increased expression of high-mobility group box 1 (HMGB1); co-inhibition of two HMGB1 receptors, receptor for advanced glycosylation end products (RAGE) and Toll-like receptor 4 (TLR4), suppressed autophagy activation by upregulating the PI3K/AKT/p70 ribosomal S6 protein kinase (p70S6K) axis and sensitized pancreatic cancer cells to PEF. We prepared a polymeric micelle formulation (M-R/T) encapsulating inhibitors of both RAGE and TLR4. The combination of IRE and M-R/T (equivalent to RAGE inhibitor at 10.4 mg/kg and TLR4 inhibitor at 5.7 mg/kg, intravenous or intraperitoneal injection every other day) significantly promoted tumor apoptosis, suppressed cell cycle progression, and prolonged animal survival in pancreatic tumor models. This study suggests that disruption of HMGB1-mediated autophagy with nanomedicine is a promising strategy to enhance the response of pancreatic cancer to IRE.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1757-1771"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424537","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":"Chemoproteomics reveals proteome-wide covalent and non-covalent targets of withaferin A.","authors":"Hui-Jun Nie, Ying-Jie Fu, Shang Long, Jia-Yu Wang, Wen-Si Zhao, Lin-Hui Zhai, Yin-Long Yang, Min-Jia Tan, Hao Hu, Xiao-Hua Chen","doi":"10.1038/s41401-024-01468-5","DOIUrl":"10.1038/s41401-024-01468-5","url":null,"abstract":"<p><p>Withaferin A (WA), a natural product used in traditional medicine, has recently garnered attention because of its diverse pharmacological effects. However, the direct targets responsible for these effects remain elusive. The discovery of targets is usually serendipitous and research has predominantly concentrated on covalent interactions, overlooking non-covalent targets. The unbiased and proteome-wide mapping of WA-interacting proteins in living cells remains largely unexplored. We have developed a chemical proteomics platform that enabled profiling of the covalent/non-covalent interactome and target occupancy in disease-related cells, which was used to reveal the landscape of the targets of WA in triple-negative breast cancer (TNBC) cells. Analysis of the discovered high-occupancy targets suggested that WA was substantially involved in the RNA metabolism pathway, in addition to other biological processes. Moreover, we biochemically validated a selection of previously unknown high-occupancy targets from various important biological pathways, including the non-covalent target MVK and covalent targets HNRNPF and CKAP4, which all play critical roles in TNBC. Collectively, these findings provided a target map for comprehensive understanding of the anti-TNBC activity of WA, and present WA-targetable proteins as new avenues for pharmacological intervention in TNBC. We anticipate that this platform will be applicable for the unbiased profiling of the targets of WA in various other disease-related cell models, as well as for other bioactive electrophilic natural products in different pathophysiological systems.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1782-1793"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121769","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}