Acta Pharmacologica Sinica最新文献

{"title":"Isoginkgetin, a natural biflavonoid from Ginkgo biloba, inhibits inflammatory response in endothelial cells via suppressing NF-κB activation.","authors":"Mei-Jie Chen, Zhi-Dan Zhang, Fan-Shun Zhang, Paul C Evans, Hans Strijdom, Suo-Wen Xu","doi":"10.1038/s41401-025-01612-9","DOIUrl":"https://doi.org/10.1038/s41401-025-01612-9","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648227","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":"Senkyunolide A ameliorates cholestatic liver fibrosis by controlling CLCC1-mediated endoplasmic reticulum Ca²⁺ release.","authors":"Ya-Jing Li, Meng-Yu Guo, Wen-Qing Qin, Jia-Nan Li, Yu-Fei Li, Fu-Kun Zhang, Xiao-Yong Xue, Shuo Li, Jiao-Rong Qu, Run-Ping Liu, Lei Wang, Xiao-Jiao-Yang Li","doi":"10.1038/s41401-025-01615-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01615-6","url":null,"abstract":"<p><p>Cholestatic liver disease is characterized by highly accumulated bile acids and cholangiocyte proliferation, resulting in the development of fibrosis, cirrhosis, and ultimately liver failure necessitating liver transplantation. Calcium (Ca²⁺) signaling is commonly dysregulated in cholestasis and serves as an important regulator mediating cell proliferation. However, the role of Ca²⁺-mediated cholangiocyte proliferation and treatment strategies in bile duct ligation (BDL)-induced liver injury remains poorly understood. By integrating transcriptomic analysis with molecular biology techniques, we explored the mechanisms of liver injury across BDL animal models, primary cholangiocytes, and human intrahepatic biliary epithelial cholangiocytes. Here, we found that a natural ingredient, senkyunolide A (SenA), effectively alleviated cholestasis-induced Ca²⁺ release from ER by inhibiting RYR channel, thereby preventing FIP200-mediated ER autophagy in response to Ca²⁺ transients on the cytosolic ER surface. Increased cytosolic Ca²⁺ further triggered ER stress, cholangiocyte cycle progression, and ductular reaction (DR). Importantly, SenA reversed the above process through its binding to chloride Channel CLIC Like 1 (CLCC1) for ubiquitination, thereby inhibiting CLCC1 activity and ER Ca²⁺ release. si-CLCC1-loaded liposomes targeting cholangiocytes enhanced the anti-DR effects of SenA. Collectively, by controlling ER release of Ca²⁺ in cholangiocytes, SenA presents potential for the development of therapeutic strategies aimed at addressing cholestatic fibrosis. SenA inhibited Ca²⁺-mediated cholangiocyte proliferation by binding to and promoting the ubiquitination of CLCC1, thereby alleviating cholestatic liver fibrosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641448","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":"PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis.","authors":"Dan Li, Jia-Hao Li, Ying-Ying Guo, Ya-Jie Chen, Meng Zhang, Fei-Xue Xu, Wan-Yi Li, Qi-Zhu Tang","doi":"10.1038/s41401-025-01613-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01613-8","url":null,"abstract":"<p><p>Myocardial remodeling is critical pathological processes in various cardiovascular diseases, where redox imbalance and mitochondrial bioenergetic perturbations emerge as key determinants. Prohibitin 2 (PHB2), which resides in the mitochondrial inner membrane, serves as a critical regulator of mitochondrial homeostasis. In this study we investigated the protective role of PHB2 in transverse aortic constriction (TAC)-induced cardiac remodeling with a particular focus on its ability to safeguard the heart by improving mitochondrial function and alleviating oxidative stress. We revealed that PHB2 expression was significantly decreased in the heart of TAC mice and in Ang II (1 μM)-treated cardiomyocytes. Cardiac-specific PHB2 overexpression mitigated TAC-induced cardiac remodeling, improving cardiac function and attenuating hypertrophy. Additionally, PHB2 overexpression effectively suppressed oxidative stress in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Furthermore, PHB2 overexpression restored mitochondrial function in Ang II-treated cardiomyocytes evidenced by elevated ATP levels and enhanced oxidative phosphorylation capacity. IP-MS analysis revealed that PHB2 directly interacted with Transporter of Outer Mitochondrial Membrane 40 (TOMM40) to regulate mitochondrial function. Importantly, silencing TOMM40 abolished the protective effects of PHB2. We demonstrated that PHB2 preserves TOMM40 protein levels predominantly through inhibition of ubiquitin-dependent proteasomal degradation. Collectively, we discover a new function of PHB2 in safeguarding mitochondrial morphofunctional homeostasis in response to pathological stress through facilitating TOMM40 stabilization, suggesting PHB2 as a promising therapeutic target for potential interventions in heart diseases. Schematic illustration of PHB2's potential protective mechanism against cardiac hypertrophy. PHB2 protects against pressure overload-induced cardiac hypertrophy through preserving TOMM40 protein to maintain mitochondrial energetic homeostasis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635903","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":"Co-delivery of shikonin and JQ1 inhibits triple-negative breast tumor progression and lung metastasis through inhibition of epithelial-mesenchymal transition and vasculogenic mimicry.","authors":"Xing-Yu Xu, Dipika Ramdas Kalambhe, Yue Yu, Ling-Xi Yu, Zhi-Wen Gu, Xiao-Ying Jin, Hui-Yuan Wang, Yong-Zhuo Huang","doi":"10.1038/s41401-025-01605-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01605-8","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is highly prone to lung metastasis, primarily driven by epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM). Therefore, inhibiting EMT and VM represents a promising therapeutic strategy for TNBC. The immunosuppressive tumor microenvironment contributes substantially to poor treatment outcomes, with M2-type macrophages secreting excessive levels of TGF-β that promote both EMT and VM. In this study, we proposed a combination therapy strategy involving shikonin (SHK) and JQ1 delivered via a mesoporous polydopamine-based Pickering emulsion (termed MPDA@PE). This formulation significantly suppressed tumor growth and lung metastasis by inducing apoptosis in TNBC and inhibiting TGF-β-induced EMT and VM. Furthermore, MPDA@PE can be incorporated into a thermosensitive hydrogel for application in the prevention of TNBC recurrence and lung metastasis following surgical resection. These findings highlight a potential therapeutic approach for effective TNBC treatment. The combined administration of SHK and JQ1 inhibits both EMT and VM. This approach disrupts the nutrient supply in tumor tissues by blocking VM and suppresses tumor metastasis through EMT inhibition. Consequently, it demonstrates therapeutic efficacy against TNBC recurrence post-surgery and effectively limits lung metastasis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635901","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":"Discovery of selective GluN1/GluN3A NMDA receptor inhibitors using integrated AI and physics-based approaches.","authors":"Shi-Wei Li, Yue Zeng, Sa-Nan Wu, Xin-Yue Ma, Chao Xu, Zong-Quan Li, Sui Fang, Xue-Qin Chen, Zhao-Bing Gao, Fang Bai","doi":"10.1038/s41401-025-01607-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01607-6","url":null,"abstract":"<p><p>N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels essential for synaptic transmission and plasticity in the central nervous system. GluN1/GluN3A, an unconventional NMDAR subtype functioning as an excitatory glycine receptor, has been implicated in mood regulation, with high expression in brain regions governing emotional and motivational states. However, therapeutic exploration has been significantly hindered by a lack of potent and selective modulators, limited structural data and the intrinsic complexity of ion channels. Here, we introduce a compound virtual screening pipeline that combines artificial intelligence and physical models, integrating two sequence-based deep learning prediction models (TEFDTA and ESMLigSite) with a molecular docking approach. This approach was employed to identify potential inhibitors against GluN1/GluN3A by screening a commercial database containing 18 million compounds. The strategy resulted in an impressive hit rate of 50% for discovering inhibitors, with the most promising compound exhibiting strong inhibitory activity (IC₅₀ = 1.26 ± 0.23 μM) and remarkable target specificity (>23-fold selectivity over the GluN1/GluN2A receptor). These findings highlight the effectiveness of AI-assisted strategies in addressing challenges related to unconventional ion channels and pave the way for new therapeutic exploration.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635902","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":"SERCA2 regulates Piezo1 channel activation and contributes to the cardiac function and baroreflex in mice.","authors":"Jia-Xin Zhao, Yin-Zhi Xu, Hui-Xiao Fu, Jia-Qun Li, Mao Yue, Zhao-Yuan Xu, Xue-Lian Li, Chang-Peng Cui, Bai-Yan Li","doi":"10.1038/s41401-025-01610-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01610-x","url":null,"abstract":"<p><p>Piezo1 channels play important roles in physiological processes such as tactile sensation, blood pressure (BP) control, cardiac development, inflammatory responses as well as in disease processes. Sarco-endoplasmic reticulum Ca²⁺-transporting ATPase (SERCA) is the only active protein in the SR that orchestrates calcium homeostasis by translocation of Ca²⁺ from the cytoplasm to the sarcoplasmic reticulum. It has been shown that SERCA2 inhibits Piezo1 function in mammals by directly acting on the Piezo1 mechano-transduction module of mechanosensitive ion channels. In this study, we investigated whether SERCA2 regulates Piezo1 activation indirectly by modulating Ca²⁺ homeostasis. We showed that treatment with a Piezo1 agonist Yoda1 (5 µM) markedly increased the viability and ATP synthesis of primary cardiomyocytes as well as intracellular Ca²⁺ content through activation of Piezo1, and upregulated the expression of Piezo1 and SERCA2 in the cardiomyocytes. However, si-Piezo1 transfection resulted in downregulation of SERCA2 expression with opposite effects on viability and ATP synthesis and intracellular Ca²⁺ content that could not be reversed by application of Yoda1. Interestingly, application of a SERCA2 channel inhibitor paxilline (Pax, 10 µM) reversed the inhibitory effect of si-Piezo1 transfection on cardiomyocyte function. Using patch clamping and Ca²⁺ transient analyses in cardiomyocytes, we demonstrated that application of Pax inhibited Yoda1-mediated Ca²⁺ currents and APD₅₀, confirming that Piezo1 activation by Yoda1 was significantly inhibited by Pax. Furthermore, application of Yoda1 was able to reverse si-SERCA2 transfection-induced impairment of myocardial function. Microinjection of Yoda1 and Pax into nodose ganglion (NG) in HFD-HTN model rats also demonstrated that the effect of Yoda1 was inhibited in the presence of Pax, thus confirming that Pax inhibited intracellular Ca²⁺ recycling by SERCA2. These results demonstrate for the first time that the application of Pax inhibits the recycling of intracellular Ca²⁺ by SERCA2 and reverses the reduction in cardiomyocyte function caused by downregulation of Piezo1 expression.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590214","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 update for AlphaFold3 versus experimental structures: assessing the precision of small molecule binding in GPCRs.","authors":"Shi-Yi Shen, Jun-Rui Li, Yu-Song Wang, Shao-Ning Li, H Eric Xu, Xin-Heng He","doi":"10.1038/s41401-025-01617-4","DOIUrl":"https://doi.org/10.1038/s41401-025-01617-4","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are key drug discovery targets with many of them modulated by small molecules via diverse binding mechanisms. AlphaFold3, a leading structure prediction tool, models GPCR-small molecule complexes, but its accuracy remains insufficiently evaluated. In this study we compared 74 AlphaFold3-predicted structures to experimental counterparts. We showed that while AlphaFold3 accurately captured global receptor architecture and orthosteric binding pockets, which was consistent with our previous research, its ligand positioning was highly variable and often inaccurate, rendering predictions unreliable, particularly for allosteric modulators. The significant divergence from experimental structures, particularly for complex ligand interactions, highlighted AlphaFold3's limitations and underscored that experimental structures remained essential for validating ligand-binding accuracy in GPCR complexes. These findings suggest that while AlphaFold3 offers potential for structure-based drug design, its current inaccuracies necessitate substantial refinement and integration with experimental data. This study highlights the limitation of AlphaFold3 in predicting small molecule binding and reinforces the critical role of high-resolution experimental validation for reliable GPCR-ligand interactions.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599073","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":"Tetrandrine augments melanoma cell immunogenicity via dual inhibition of autophagic flux and proteasomal activity enhancing MHC-I presentation.","authors":"Li-Na He, Yu-Jiao Liu, Jun-Bo Jiang, Ding-Ye Wang, Yu-Ling Li, Shi-Ji Zeng, Zi Guo, Pei-Yan Yao, Zi-Chang Lin, Si-Xian Lv, Xiao-Yi Liu, Wei Guo, Fang Liu, Biao-Yan Du, Ting-Xiu Zhao, Jian-Yong Xiao, Ya-Fei Shi, Kun Wang","doi":"10.1038/s41401-025-01507-9","DOIUrl":"10.1038/s41401-025-01507-9","url":null,"abstract":"<p><p>MHC-I-mediated antigen presentation is pivotal in antitumor immunity, enabling the recognition and destruction of tumor cells by CD8⁺ T cells. Both the proteasome and autophagy serve as essential cellular degradation mechanisms that regulate the stability and functionality of MHC-I molecules. In melanoma, modulating the pathways that affect MHC-I antigen presentation is pivotal and can profoundly influence the therapeutic outcomes of immunotherapy. Our initial effort of this study was a screening process to identify natural compounds capable of amplifying MHC-I surface expression on B16 melanoma cells. Utilizing flow cytometry with fluorescently tagged antibodies, we identified tetrandrine (Tet), a bisbenzylisoquinoline alkaloid derived from the root of Stephania tetrandra, as a potent enhancer of MHC-I-mediated antigen presentation in B16 melanoma cells. We demonstrate that tetrandrine (2.5, 5, 7.5 μM) dose-dependently upregulates both surface and total MHC-I protein levels in B16 or A375 melanoma cells by simultaneously inhibiting autophagy and proteasomal activity, two key pathways involved in MHC-I degradation. This dual inhibition stabilizes MHC-I molecules, leading to enhanced tumor antigen presentation and improved recognition by CD8⁺ T cells. In co-culture systems, tetrandrine treatment increased CD8⁺ T cell activation and cytotoxicity against melanoma cells, evidenced by elevated IFN-γ secretion and increased tumor cell apoptosis. Administration of tetrandrine (50 mg·kg^-1·d^-1, i.g., for 15 days) significantly suppressed melanoma growth in mouse models accompanied by increased CD8⁺ T cell infiltration and activation within the tumor microenvironment. Notably, tetrandrine synergized with anti-PD-1 immune checkpoint therapy, leading to enhanced tumor growth inhibition compared to either treatment alone. We revealed that tetrandrine (7.5 μM) blocked the lysosomal calcium efflux channel TPC2, disrupting lysosomal calcium homeostasis, thus impairing lysosomal acidification and proteasomal activity, thereby stabilizing MHC-I molecules and promoting antigen presentation. These results highlight tetrandrine's unique mechanism of action in enhancing MHC-I-mediated antigen presentation through dual inhibition of autophagic flux and proteasomal degradation. This study underscores tetrandrine's potential as a novel immunomodulatory agent to boost CD8⁺ T cell-mediated tumor cell eradication and enhance the efficacy of immune checkpoint therapies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2056-2072"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522401","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":"FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways.","authors":"Dong-Xue Wang, Wen-Ting Huang, Jun-Feng Shi, Fei Liu, Wen-Yi Jiang, Ke-Yang Chen, Shu-Yang Zhang, Xiao-Kun Li, Li Lin","doi":"10.1038/s41401-024-01462-x","DOIUrl":"10.1038/s41401-024-01462-x","url":null,"abstract":"<p><p>Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21^-/- tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1834-1851"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530896","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":"Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway.","authors":"Jin-Xuan Su, Hai-Xia Zhou, Zhi-Jing Zhang, Xiao-Feng Zhou, Qiu-Ming Zou, Si-Jia Li, Xiao-Song Zhuang, Jian-Qin Lai, Si-Yu Yang, Kai Cui, Yong-Qi Liu, Rui-Jie Yuan, Heng-Xin Pan, Zi-Sheng Li, Han-Yun Tu, Mei Cheng, Yu Yan, Qi Qi, Yu-Bo Zhang","doi":"10.1038/s41401-025-01514-w","DOIUrl":"10.1038/s41401-025-01514-w","url":null,"abstract":"<p><p>Gene therapy, epigenetic therapies, natural compounds targeted therapy, photodynamic therapy, nanoparticles, and precision medicines are becoming available to diagnose and treat cancer. Gracillin, a natural steroidal saponin extracted from herbs, has shown potent efficacy against a range of malignancies. In this study, we investigated the molecular anticancer mechanisms of gracillin. We showed that gracillin dose-dependently suppressed proliferation, migration, and invasion in breast cancer, liver cancer, and glioblastoma cells with IC₅₀ values around 1 μM, which were associated with MST-independent activation of Hippo signaling pathway and subsequent decreased YAP activity. We demonstrated that gracillin activated the Hippo signaling by inducing Merlin/LATS protein-protein interaction (PPI). A competitive inhibitory peptide (SP) derived from the binding interface of the PPI, disrupted the interaction, abolishing the anticancer activity of gracillin. In nude mice bearing MDA-MB-231, HCCLM3, or U87MG xenograft tumor, administration of gracillin (5, 10 mg·kg^-1·d^-1, i.g. for 21 days) dose-dependently suppressed the tumor growth, associated with the induced Merlin/LATS PPI, activated Hippo signaling, as well as decreased YAP activity in tumor tissues. Our data demonstrate that gracillin is an efficacious therapeutic agent for cancer treatment, induction of Merlin/LATS PPI might provide proof-of-concept in developing therapeutic agent for cancer treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2016-2028"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584238","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}