Acta Pharmacologica Sinica最新文献

{"title":"Human germline-like monoclonal antibody against 5T4 enables potent ADC and CAR-T therapies for solid tumors.","authors":"Yi-Qing Jiang, Xiao-Jie Ma, Yin-Man Wang, Yi Feng, Yu Kong, Ai-Ling Huang, Zi-Xuan Jin, Tian-Lei Ying, Yan-Ling Wu","doi":"10.1038/s41401-025-01731-3","DOIUrl":"10.1038/s41401-025-01731-3","url":null,"abstract":"<p><p>5T4 is an oncofetal antigen overexpressed in a wide range of solid tumors with minimal presence in normal adult tissues, highlighting its promise as a therapeutic target. In this study, we identified germline-like human monoclonal antibodies targeting human 5T4 with high affinity, among which antibody m603 exhibits superior cell binding activity to various cancer cells including breast, pancreatic, ovarian, lung and liver cancer cell lines. Subsequently, we constructed antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-T cell based on m603. By conjugating the antibody with cytotoxic payload DM4 or MMAE, the resulting ADCs demonstrated potent and antigen-dependent cell killing activity in vitro. The ADC conjugated with MMAE payload elicited durable tumor suppression in pancreatic cancer xenograft models. Furthermore, third-generation CAR-T cells derived from m603 (603z-CAR-T), incorporating 4-1BB and CD28 costimulatory domains, effectively induced IFN-γ and IL-2 secretion and remarkable tumor eradication. The germline-like antibody as a versatile platform for 5T4-targeted therapies offers promising immunotherapies for treating solid tumors.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1326-1337"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058490","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":"Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation.","authors":"Xiao-Jun Zhao, Yang Xu, Cong-Hui Zhang, Cong Zhao, Li Liu, Xiao-Wei Wang, Meng-Yan Wang, Zi-Xiang Gao, Rong-Guang Shao, Li-Qiang Qi, Yong-Sheng Che, Wu-Li Zhao","doi":"10.1038/s41401-025-01730-4","DOIUrl":"10.1038/s41401-025-01730-4","url":null,"abstract":"<p><p>Mitochondrial DNA (mtDNA) mutations are the most common cause in aberrant mitochondrion-leading cancer, exploration of direct targeting mutated mtDNA still remains incomplete. Secoemestrin C (Sec C) is epitetrathiodioxopiperazine derived from the endophytic fungus, which exhibited a rapid and prominent anti-breast cancer effect in triple-negative breast cancer (TNBC). In this study we investigated the anticancer mechanism of Sec C, especially its effect on TNBC cells. We showed that Sec C potently inhibited the viability of both TNBC (MDA-MB-231, HS578T, BT-549) and non-TNBC (MCF-7, T47D, SK-BR-3) cells in vitro with IC₅₀ values of 1-2 μM. In MDA-MB-231 cells, treatment with Sec C (2 μM) induced DNA breakage and subsequent apoptosis. Furthermore, treatment with Sec C (2 μM) caused mtDNA damage, mitochondrial ubiquitination and subsequent mitophagy in MDA-MB-231 and MCF-7 cells. RNA-seq analysis revealed that Sec C mitigated YAP level in time and dose-dependent manner either in MDA-MB-231 and MCF-7 cells. By re-analyzing the Sec C-responsive gene network proteins, we identified SLX4 as an oncogene promoting breast cancer development, potentially by stabilizing mtDNA to suppress pathologic mitochondrion mitophagy. Specifically, Sec C initiated MDA-MB-231 cells to yield ROS that induced SLX4 ubiquitination and degradation, leading to mtDNA damage and exacerbated mitophagy and promoted YAP degradation bypassing YAP-driven DNA repair pathways. This study not only demonstrates that Sec C is a rapid and prominent anti-breast cancer drug for TNBC, but also reveals SLX4 as a novel mtDNA stabilizer supporting breast cancer progression, positioning it as both a prognostic biomarker and therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1270-1284"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958553","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":"MicroRNA-129-5p in the mPFC is involved in the chronic mild stress-induced depression-like behaviors in rats.","authors":"Jing-Yi Xu, Chen-Chen Li, Hao-Chen Zhang, Li-Jie Guo, Meng-Yu Geng, Xiang-Jun He, Li-Yong Wang, Hui Li, Yong-Jun Wang, Zhi-Qing David Xu, Yu-Tao Yang","doi":"10.1038/s41401-025-01708-2","DOIUrl":"10.1038/s41401-025-01708-2","url":null,"abstract":"<p><p>Current treatments for depression have focused on improving the dysregulated monoamine neurotransmitter systems in the brain. However, the conventional antidepressants based on the monoamine hypothesis usually exert side effects and unsatisfactory responses. MicroRNAs (miRNAs) are smaller noncoding RNA which are highly expressed in the brain and play important roles in the development of neurological disorders. In this study we investigated the role of miRNAs in the occurrence of depression. A rat depression model was established by exposure to chronic mild stress (CMS) over 4 weeks. In the next week, the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were used to evaluate the depression-like behaviors. Then the rats were euthanized and total RNA was isolated from rat mPFC. We showed that the level of microRNA-129-5p (miR-129-5p) was significantly increased in the mPFC of CMS rats. Overexpression of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p virus (OE-miR-129-5p) induced the depression-like behaviors in control rats, accompanied with the impairment in neuronal structures and a decrease in synaptic plasticity. In contrast, knockdown of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p sponge virus (KD-miR-129-5p) ameliorated the depression-like behaviors in CMS rats, along with the improvement in neuronal structures and an increase in synaptic plasticity. Furthermore, we demonstrated that miR-129-5p targeted to the brain-derived neurotrophic factor (BDNF) in the mPFC to contribute to the development of depression. This study suggests that miR-129-5p in the mPFC impairs the neuronal structures and reduces the synaptic plasticity after the exposure to CMS, which underlies the development of CMS-induced depression-like behaviors in rats.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1149-1161"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987711","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":"Clozapine impaired the hypoglycemic effect of metformin by inhibiting hepatic organic cation transporter 1 (OCT1).","authors":"Wen-Han Wu, Yi-Dong Dai, Wen-Ke Feng, Hao-Ran Chen, Xin-Yue Zhu, Ling Jiang, Xiao-Dong Liu, Li Liu","doi":"10.1038/s41401-025-01707-3","DOIUrl":"10.1038/s41401-025-01707-3","url":null,"abstract":"<p><p>Atypical antipsychotics often cause hyperglycemia, with clozapine showing the highest risk. Metformin is a first-line medication for managing diabetes or prediabetes and is often used to control clozapine-induced hyperglycemia. Clinical studies, however, have reported metformin resistance in some clozapine-treated patients, but the underlying mechanism remains unclear. In this study, we investigated the mechanism by which clozapine impaired the hypoglycemic effect of metformin and developed a mechanism-based semi-PBPK-PD model to predict the effect of clozapine on the pharmacokinetics and hypoglycemic effect of metformin in rats. Rats received clozapine (50 mg·kg^-1·d^-1, i.g.) for 7 days. The rats received metformin (200 mg/kg, i.g.) at 0.5 h after the last dose on D7. IPGTT or pharmacokinetics study was performed at 0.5 h after the administration of metformin. We showed that clozapine impaired the hypoglycemic effect of metformin during the glucose tolerance test without altering the plasma exposure of metformin in the rats. The liver is the main target for the hypoglycemic effect of metformin. We showed that clozapine significantly reduced the hepatic distribution of metformin, inhibited metformin uptake in rat livers and rat primary hepatocytes, and inhibited the glucose consumption enhanced by metformin in rat primary hepatocytes. OCT1 mediates the hepatic uptake of metformin. We demonstrated that clozapine dose-dependently inhibited metformin uptake in HEK293-OCT1 cells with the IC₅₀ value of 8.9 μM. Silencing OCT1 in rat primary hepatocytes impaired metformin uptake and attenuated the enhanced glucose consumption by metformin, suggesting that clozapine impaired the hypoglycemic effect of metformin by inhibiting OCT1-mediated hepatic uptake. Subsequently, a semi-PBPK-PD model was constructed based on this mechanism. The model well predicted the decreased hepatic exposure and hypoglycemic effect of metformin in the rat co-administered with clozapine.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1338-1350"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916359","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":"A structural overview of G-protein-coupled receptors in neurological disorders.","authors":"Oindrilla Dutta Gupta, Indranil Chakraborty, Kuntal Pal","doi":"10.1038/s41401-025-01712-6","DOIUrl":"10.1038/s41401-025-01712-6","url":null,"abstract":"<p><p>Neuropsychiatry and neurodegenerative disorders (NPDs and NDDs) are often associated with various physiological factors. It is increasingly apparent that signal transducers like G-protein-coupled receptors (GPCRs) are critical in disease progression and constitute an important class of drug targets. Several members of class A, class B, and class C GPCR families, along with their cognate binding partners, are involved in neurotransmission and neuromodulation. The vast information about the different molecular states of these GPCRs with their signaling complexes unravels the understanding of residual specificity in these protein-protein interactions and the dynamicity of transmembrane helices. The atypical mode of interaction of GPCRs with binding partners provides valuable insights for GPCR-conformation-based drug designing. In this review, we highlight the structural features of the serotonin, dopamine, and corticotropin receptors, namely 5-HTR_1A, 5-HTR_1B, 5-HTR_2A, 5-HTR_2B, 5-HTR_2C, 5-HTR₄, 5-HTR₆, 5-HTR₇, D_1-5R, and CRF_1-2R when forming transient complexes with G-proteins and arrestins. The distinct structural characteristics of these receptors explain the underlying molecular mechanism for signaling specificity and related physiological processes. This review also summarizes the importance of these structural insights in developing newer and effective pharmacologically biased drugs that can mediate specific signaling pathways to GPCRs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1077-1102"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083861","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":"PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin.","authors":"Javier Jurado-Aguilar, Emma Barroso, Patricia Rada, Mona Peyman, Adel Rostami, Jesús Balsinde, Ángela M Valverde, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera","doi":"10.1038/s41401-025-01705-5","DOIUrl":"10.1038/s41401-025-01705-5","url":null,"abstract":"<p><p>Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, increases the circulating levels of the metabolic regulator growth differentiation factor 15 (GDF15) via transcriptional regulation, with the kidneys being responsible for this increase. Since peroxisome proliferator-activated receptor (PPAR)β/δ agonists mimic many of the effects of metformin, including the rise in circulating GDF15 levels, we herein investigated whether the metformin-mediated antidiabetic effects and GDF15 upregulation were dependent on this nuclear receptor. Male Ppard^-/- and wild-type (WT) mice received a western-type high-fat diet (HFD) for 12 weeks and were treated with metformin (200 mg ·kg^-1 ·d^-1, i.g.) in the last 3 weeks. At the end of the treatment, the mice were sacrificed, and the skeletal muscle, kidney, and liver samples were collected for analyses. We showed that metformin treatment ameliorated glucose intolerance and increased hepatic and circulating GDF15 levels in WT mice, but not in Ppard^-/- mice fed a HFD. In the kidneys, metformin treatment increased the expression levels of phosphorylated AMPK and GDF15 in the WT mice, which was abolished in the Ppard^-/- mice. Both β-arrestin 1 and proprotein convertase subtilisin/kexin type 6 (PCSK6) are involved in the posttranslational maturation of GDF15. Likewise, metformin treatment increased the levels of β-arrestin 1 and PCSK6 in the kidneys of WT mice, but not Ppard^-/- mice. Furthermore, treatment of mice with a PPARβ/δ activator, GW501516 (3 mg· kg^-1 ·d^-1, i.g., for 7 days), increased the levels of these proteins in the kidneys and liver. In contrast, a PPARβ/δ antagonist GSK0660 (50 µM) prevented the increase in GDF15, β-arrestin 1, and PCSK6 levels caused by metformin in cultured podocytes. Collectively, these data uncover a regulatory axis wherein metformin, via PPARβ/δ, orchestrates glucose tolerance, AMPK activity, and GDF15 maturation.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1219-1232"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987690","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":"Deficient chaperone-mediated autophagy drives multiorgan fibrogenesis via SMAD2/4 stabilization to sustain TGFβ-SMAD signaling.","authors":"Jia-Yuan Jin, Yu-Xuan Song, Jia-Bin Lu, Guan-Qun Li, Jun-Qiang Wang, Xue-Jing Feng, Pei-Hua Luo, Bo Yang, Zhi-Fei Xu, Hao Yan, Qiao-Jun He, Xiao-Chun Yang","doi":"10.1038/s41401-026-01807-8","DOIUrl":"https://doi.org/10.1038/s41401-026-01807-8","url":null,"abstract":"<p><p>Fibrotic diseases, driven by excessive extracellular matrix deposition, account for substantial global morbidity and mortality, yet effective therapies remain elusive. Emerging evidence highlights impaired protein homeostasis as a key contributor to fibrosis, prompting exploration of autophagy-mediated degradation pathways. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective lysosomal degradation mechanism, in fibrosis progression. We demonstrate that CMA activity is suppressed in fibrotic tissues from experimental mice and human patients, correlating with pathological SMAD2/4 accumulation. Mechanistically, CMA deficiency impedes SMAD2/4 degradation, amplifying TGF-β signaling and collagen overproduction. AAV-mediated LAMP2A overexpression to restore CMA activity alleviated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced hepatic fibrosis in mice. Furthermore, we identify sunitinib, an FDA-approved tyrosine kinase inhibitor, as a novel CMA activator that enhances LAMP2A transcription via targeting the transcription factor JUND, reduces SMAD2/4 levels, and mitigates fibrosis in vivo. Our findings establish CMA dysfunction as a common pathological hallmark of fibrotic diseases and unveil therapeutic strategies targeting CMA to restore protein homeostasis. This study provides critical insights into fibrosis pathogenesis and positions pharmacological CMA activation as a promising treatment avenue. CMA is impaired across fibrotic tissues, driving disease progression. Sunitinib activates CMA by targeting JUND to promote SMAD2/4 degradation, suppressing TGFβ-SMADs-fibrosis signaling. CMA, chaperone-mediated autophagy; IPF, idiopathic pulmonary fibrosis; PF, pulmonary fibrosis; HF, hepatic fibrosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809146","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":"Resibufogenin promotes angiogenesis via the VAV3-mediated ITGA5-VEGF signaling axis in macrophages to alleviate myocardial infarction.","authors":"Ran Wang, Guo-Qiang Lin, Fei-Yun Wang, Yao Chen, Shou-Jiao Peng, Jian-Ge Zhang","doi":"10.1038/s41401-026-01799-5","DOIUrl":"https://doi.org/10.1038/s41401-026-01799-5","url":null,"abstract":"<p><p>Myocardial infarction (MI) continues to be a leading cause of global mortality. Resibufogenin (RBG), a principal bioactive constituent derived from Venenum Bufonis, is well recognized for its potent cardiotonic properties. Nevertheless, the therapeutic potential of RBG in the context of MI remains to be fully elucidated. This study revealed that RBG exerted significant cardioprotective effects in a murine model of MI by preserving cardiac function, attenuating myocardial injury, and increasing vascular density. Proteomic analysis revealed that angiogenesis was the predominant biological process associated with RBG-responsive proteins. Integrated proteomic analysis and mechanistic validation demonstrated that RBG activated the ITGA5-VEGF signaling axis, a pathway essential for its therapeutic efficacy, in a macrophage-dependent manner. Notably, both pharmacological inhibition of ITGA5 and depletion of macrophages completely abrogated RBG-mediated cardioprotection in the MI model. Furthermore, RBG significantly increased endothelial cell proliferation, migration, and tube formation in a macrophage-endothelial cell coculture system. More importantly, RBG upregulated ITGA5 expression in macrophages through activation of the VAV3/CDC42 signaling pathway. Collectively, these findings demonstrate that RBG is a promising therapeutic agent for myocardial infarction and acts via the macrophage-specific VAV3/CDC42-mediated ITGA5/VEGF signaling pathway to promote reparative angiogenesis. This study elucidates the cardioprotective effects and underlying mechanisms of RBG and establishes a scientific basis for the discovery of novel therapeutic agents from natural products.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759337","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":"Targeting endoplasmic reticulum stress and YAP/TAZ-SMAD1/5 signaling to ameliorate endothelial dysfunction in diabetes.","authors":"Yan Zhou, Yifan Yang, Yuehan Wang, Wai San Cheang","doi":"10.1038/s41401-026-01802-z","DOIUrl":"https://doi.org/10.1038/s41401-026-01802-z","url":null,"abstract":"<p><p>YAP/TAZ and SMAD1/5 signaling modulate atherosclerosis. These involvements in diabetes-associated endothelial dysfunction remain unexplored, thereby being investigated from different endothelial cells and a total of 102 mice in the current study. Male C57BL/6 mice were fed a high-fat diet (45% kcal% fat, 15 weeks) and orally administered with endoplasmic reticulum (ER) stress alleviator 4-phenylbutyric acid (100 mg·kg^-1·d^-1) and jatrorrhizine (50 mg·kg^-1·d^-1) for 5 weeks. Endothelial cells were cultured with high glucose, ER stress inducer tunicamycin, ER stress alleviators, YAP inhibitor simvastatin, or jatrorrhizine. The mouse aorta was divided into the aortic arch and thoracic aorta regions to investigate the regional difference. Treatment with PBA and jatrorrhizine ameliorated endothelium-dependent relaxations as well as inhibited ER stress, YAP/TAZ-SMAD1/5 signaling and oxidative stress in aortas. Phosphorylation of YAP/TAZ was highly expressed in the thoracic aorta but low in the aortic arch. On the other hand, phosphorylation of SMAD1/5 was upregulated in the inner curvature of the aortic arch but downregulated in the thoracic aorta. In HUVECs, ER stress alleviators significantly inhibited YAP/TAZ-SMAD1/5 signaling and increased NO bioavailability, but the YAP inhibitor did not suppress ER stress. Inhibition of YAP/TAZ downregulated SMAD1/5 signaling under high glucose stimulation, followed by the Akt/eNOS pathway. YAP/TAZ directly interacts with SMAD1/5, and their binding is significantly enhanced under high-glucose conditions. A natural compound, jatrorrhizine, was identified to inhibit YAP/TAZ-SMAD1/5 signaling and protect vascular function in diabetes. To conclude, ER stress activates YAP/TAZ and SMAD1/5 signaling, resulting in endothelial dysfunction in diabetes. Inhibition of YAP/TAZ-SMAD1/5, such as by ER stress alleviators and natural product jatrorrhizine, ameliorates endothelial dysfunction associated with diabetes. These findings support the cross-talk between ER stress and YAP/TAZ-SMAD1/5 as well as their potential as therapeutic targets.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759261","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":"TRPM7 kinase inhibitor TG100-115 provides neuroprotection against neonatal hypoxic-ischemic brain injury.","authors":"Xin-Yang Zhang, Hio Lam Ho, Zheng-Wei Luo, F David Horgen, Daniel Romo, Kenneth G Hull, Andrea Fleig, Zhong-Ping Feng, Hong-Shuo Sun","doi":"10.1038/s41401-026-01775-z","DOIUrl":"https://doi.org/10.1038/s41401-026-01775-z","url":null,"abstract":"<p><p>Hypoxic-ischemic brain injury (HIBI) is a major cause of perinatal brain damage, contributing to significant neonatal mortality and disability, yet its therapeutics remain limited. Transient receptor potential melastatin 7 (TRPM7), a channel-kinase with kinase activity involved in neuronal death and neuroinflammation, has been implicated in ischemic and hypoxic brain damage. Although the ion channel function of TRPM7 has been widely explored, the specific contribution of its kinase activity to HIBI pathophysiology remains poorly understood, mainly due to the lack of potent TRPM7 kinase inhibitors. TG100-115 (TG) is the first identified potent TRPM7 kinase inhibitor. Using a neonatal mouse model of HIBI, we examined the in vivo neuroprotective effects of TG across different treatment paradigms, including pre-treatment and post-treatment at various time points. TG significantly reduced infarct volume when administered before HIBI or up to 3 h post-HIBI, improved brain morphology, and enhanced both short- and long-term functional recovery. Mechanistically, TG treatment normalized TRPM7 protein levels, modulated caspase-3-associated apoptotic pathway, and preserved neuronal integrity. Additionally, TG attenuated the NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, indicated by reduced expression of NLRP3 and its adaptor protein ASC, as well as IL-18 levels, suggesting a role in modulating neuroinflammation. These findings demonstrate that TG protects against HIBI by modulating TRPM7 expression and apoptotic signaling, and suppressing NLRP3 inflammasome-associated neuroinflammation. This study highlights the pharmacological inhibition of TRPM7 kinase as a promising therapeutic strategy for HIBI. TG100-115, a TRPM7 kinase inhibitor, provides neuroprotection and attenuates NLRP3 inflammasome-mediated neuroinflammation in a neonatal mouse model of hypoxic-ischemic brain injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759265","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}