Acta Pharmacologica Sinica最新文献

{"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":"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":"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}

{"title":"Krüppel-like factor 9 alleviates Alzheimer's disease via IDE-mediated Aβ degradation.","authors":"Yue-Yao Feng, Jing-Ran Hao, Yu-Jie Zhang, Tong-Tong Qiu, Meng-Lin Zhang, Wei Qiao, Jin-Jin Wu, Ping Qiu, Chao-Fan Xu, Yin-Liang Zhang, Chun-Yuan Du, Zhe Pan, Yong-Sheng Chang","doi":"10.1038/s41401-025-01491-0","DOIUrl":"10.1038/s41401-025-01491-0","url":null,"abstract":"<p><p>The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer's disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9^-/-) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9^-/- mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9^-/- mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1556-1566"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439704","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":"GABA transporter 1 is a promising drug target for CUL4B mutation-associated epilepsy.","authors":"Wei Jiang, Yan-Yan Ma, Yu-Feng Wang, Shi-Qi Jin, Rui-Qi Yu, Shu-Xian Chu, Yang-Fan Gao, Mo-Lin Wang, Yong-Xin Zou, Qiao Liu, Yu Song, Yan Zheng, Chen Zhang, Gong-Ping Sun, Bai-Chun Jiang, Yao-Qin Gong","doi":"10.1038/s41401-025-01490-1","DOIUrl":"10.1038/s41401-025-01490-1","url":null,"abstract":"<p><p>Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene result in syndromic X-linked intellectual disability (XLID). In addition to intellectual disability, patients with CUL4B mutations exhibit epilepsy. To date, the mechanism underlying epilepsy associated with CUL4B mutation has not been elucidated. Here, we show that male mice with Cul4b deleted in the nervous system are more susceptible to both pentylenetetrazole (PTZ)- and kainic acid (KA)-induced epilepsy and exhibit spontaneous epilepsy without any chemical inducers. We identify the CRL4B complex as an E3 ubiquitin ligase that targets GABA transporter 1 (GAT1). CUL4B deletion in male mice results in GAT1 accumulation and increased GABA reuptake, leading to impaired GABA-mediated inhibitory synaptic transmission. Treating CUL4B-deficient mice with the GAT1 inhibitor tiagabine effectively reverses the increased susceptibility to chemical-induced epilepsy and attenuates spontaneous epilepsy without the use of chemical inducers. We further confirm the role of CUL4B in the regulation of GAT1 levels and GABA uptake in neurons and astrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from patients with CUL4B loss-of-function mutations. Our work reveals a novel mechanism underlying the pathogenesis of epilepsy and identifies a promising drug target for treating CUL4B mutation-associated epilepsy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1580-1591"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472089","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":"METTL14-mediated m⁶A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.","authors":"Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang","doi":"10.1038/s41401-025-01485-y","DOIUrl":"10.1038/s41401-025-01485-y","url":null,"abstract":"<p><p>N⁶-methyladenosine (m⁶A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m⁶A modification promotes the development and progression of cardiomyocyte pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1639-1651"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405120","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 5-imidazole-3-methylbenz[d]isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia.","authors":"Jian-Kang Hu, Xin Tang, Guo-Long Luo, Cheng Zhang, Tian-Bang Wu, Chao Wang, Hui Shen, Xiao-Fan Zhao, Xi-Shan Wu, Jeff B Smaill, Yong Xu, Yan Zhang, Qiu-Ping Xiang","doi":"10.1038/s41401-025-01478-x","DOIUrl":"10.1038/s41401-025-01478-x","url":null,"abstract":"<p><p>Inhibition of the bromodomain of the cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 is an attractive therapeutic approach in oncology, particularly in acute myeloid leukemia (AML). In this study we describe the design, optimization, and evaluation of 5-imidazole-3-methylbenz[d]isoxazoles as novel, potent and selective CBP/p300 bromodomain inhibitors. Two of the representative compounds, 16t (Y16524) and 16u (Y16526), bound to the p300 bromodomain with IC₅₀ values of 0.01 and 0.03 μM, respectively. Furthermore, 16t and 16u potently inhibited the growth of AML cell lines, particularly MV4;11 cells with IC₅₀ values of 0.49 and 0.26 μM, respectively. The potent CBP/p300 bromodomain inhibitors represent a new class of compounds for the development of potential therapeutics against AML.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1706-1721"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073258","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":"Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism.","authors":"Wei-Ting Cheng, Si-Ya Pei, Jie Wu, Yan-Jie Wang, Yong-Wen Yang, Mei-Fang Xiao, Jun Chen, Yuan-Yuan Wang, Li Wu, Ze-Bing Huang","doi":"10.1038/s41401-025-01495-w","DOIUrl":"10.1038/s41401-025-01495-w","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R^-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R^-/- mice. The gut dysbiosis in CB2R^-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R^-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R^-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1676-1691"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466623","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":"Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.","authors":"Si-Yuan Shen, Chao Wu, Zhi-Qian Yang, Ke-Xin Wang, Zhen-Hua Shao, Wei Yan","doi":"10.1038/s41401-024-01472-9","DOIUrl":"10.1038/s41401-024-01472-9","url":null,"abstract":"<p><p>The medicinal and recreational uses of Cannabis sativa have been recognized for thousands of years. Today, cannabis-derived medicines are used to treat a variety of conditions, including chronic pain, epilepsy, multiple sclerosis, and chemotherapy-induced nausea. However, cannabis use disorder (CUD) has become the third most prevalent substance use disorder globally. Cannabinoid receptors are the primary targets that mediate the effects of cannabis and its analogs. Despite their importance, the mechanisms of modulation and the full therapeutic potential of cannabinoid receptors remain unclear, hindering the development of the next generation of cannabinoid-based drugs. This review summarizes the discovery and medicinal potential of phytocannabinoids and explores the distribution, signaling pathways, and functional roles of cannabinoid receptors. It also discusses classical cannabinoid drugs, as well as agonists, antagonists, and inverse agonists, which serve as key therapeutic agents. Recent advancements in the development of allosteric drugs are highlighted, with a focus on positive and negative allosteric modulators (PAMs and NAMs) that target CB1 and CB2 receptors. The identification of multiple allosteric sites on the CB1 receptor and the structural basis for allosteric modulation are emphasized, along with the structure-based discovery of ago-BAMs for CB1. This review concludes by examining the future potential of allosteric modulators in cannabinoid drug development, noting that ongoing progress in cannabinoid-derived drugs continues to open new avenues for therapeutic use and paves the way for future research into their full medicinal potential.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1495-1510"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254037","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":"Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.","authors":"Jun-Hao Deng, Hong-Yue Li, Zi-Yang Liu, Jing-Pei Liang, Ying Ren, Yuan-Ying Zeng, Ya-Li Wang, Xin-Liang Mao","doi":"10.1038/s41401-025-01481-2","DOIUrl":"10.1038/s41401-025-01481-2","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1733-1741"},"PeriodicalIF":6.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405113","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}