Acta Pharmacologica Sinica最新文献

{"title":"Transport mechanism and drug discovery of human monocarboxylate transporter 1.","authors":"Sai Shi, Jia-Chen Li, Xiao-Yu Zhou, Zhen-Lu Li, Ya-Xin Wang, Bing-Hong Xu, Sheng Ye","doi":"10.1038/s41401-025-01517-7","DOIUrl":"10.1038/s41401-025-01517-7","url":null,"abstract":"<p><p>Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2323-2333"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646709","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":"Hepatocyte cellular repressor of E1A-stimulated genes 1 protects against acetaminophen-induced liver injury by promoting autophagy.","authors":"Qian-Ying Cheng, Miao-Miao Wu, Xiao-Li Wei, Li-Li Lu, Run-Dong Liu, Yuan-Hao Li, Ni-Na Zhu, Ya-Qun Li, Li Zuo, Hua Wang","doi":"10.1038/s41401-025-01532-8","DOIUrl":"10.1038/s41401-025-01532-8","url":null,"abstract":"<p><p>Acetaminophen-induced liver injury (AILI) accounts for a significant proportion of acute liver failure emphasizing the critical need to elucidate AILI pathogenesis and to identify effective therapeutic agents. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that plays a crucial role in maintaining liver homeostasis. Prior studies have shown that CREG1 mitigates liver injury, steatosis, and inflammation associated with multiple liver diseases. In this study we investigated the role and therapeutic potential of CREG1 in AILI. We showed that the expression levels of CREG1 were markedly elevated in livers of AILI mice and patients with drug-induced liver injury (DILI), which was also observed in primary hepatocytes treated with acetaminophen (APAP). Hepatocyte-specific CREG1 deficiency mice were more sensitive to APAP compared to Creg1^fl/fl mice, whereas AAV8-mediated CREG1 overexpression protected mice from AILI. We demonstrated that CREG1 deficiency impaired autophagy and activated inflammatory signaling pathways. Pre-administration of A769662 to activate AMPK or rapamycin to induce autophagy prevented the liver injury in Creg1^Δhep mice. Coherently, the protective effect of CREG1 overexpression against AILI could be inhibited by dorsomorphin, an AMPK inhibitor. These findings suggest that CREG1 alleviates AILI by regulating autophagy through AMPK activation, and CREG1 represents a promising therapeutics target for AILI treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2237-2250"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708029","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":"CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate TLR4/NF-κB/ROS signaling.","authors":"Yi-Hong Wen, Heng-Li Zhao, Shao-Yu Wu, Jia-Xue Jiang, Yuan Gao, Zi-Fan Wang, Xiao-Yao Liu, Fei Yu, Tao Ou, An-Zhi Zhao, Li-Wen Chen, Jin-Hua Fang, Hua-Yan Wu, Jie-Ning Zhu, Ning Ma, Jiu-Feng Sun, Xian-Hong Fang, Zhi-Xin Shan","doi":"10.1038/s41401-025-01516-8","DOIUrl":"10.1038/s41401-025-01516-8","url":null,"abstract":"<p><p>SARS-CoV-2 can encode circular RNAs (circRNAs); however, the potential effects of exogenous SARS-CoV-2 circRNAs on cardiovascular sequelae remain unknown. Three circRNAs derived from the nucleocapsid (N) gene of SARS-CoV-2, namely, circSARS-CV2-Ns, were identified for functional studies. In particular, circSARS-CV2-N1368 was shown to enhance platelet adhesiveness to endothelial cells (ECs) and inhibit EC-dependent vascular relaxation. Moreover, exogenous expression of circSARS-CV2-N1368 suppressed EC proliferation and migration and decreased angiogenesis and cardiac organoid beating. Mechanistically, we elucidated that circSARS-CV2-N1368 sponged the microRNA miR-103a-3p, which could reverse circSARS-CV2-N1368-induced EC damage. Additionally, activating transcription factor 7 (ATF7) was identified as a target gene of miR-103a-3p, and Toll-like receptor 4 (TLR4) was verified as a downstream gene of ATF7 that mediates circARS-CV2-N1368-induced activation of nuclear factor kappa B (NF-κB) signaling and ROS production in ECs. Importantly, the reactive oxygen species (ROS) scavenger NAC mitigated the circSARS-CV2-N1368-promoted EC impairment. Our findings reveal that the TLR4/NF-κB/ROS signal pathway is critical for mediating circSARS-CV2-N1368-promoted oxidative damage in ECs, providing insights into the endothelial impairment caused by circSARS-CV2-Ns.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2180-2195"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603090","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":"Aberrant neuronal excitation promotes neuroinflammation in the primary motor cortex of ischemic stroke mice.","authors":"Ting-Ting Li, Xiao-Fan Guo, Yi-Jing Zhao, Ya-Hong Cheng, Dan-Qing Xin, Yan Song, De-Xiang Liu, Zhen Wang","doi":"10.1038/s41401-025-01518-6","DOIUrl":"10.1038/s41401-025-01518-6","url":null,"abstract":"<p><p>Current treatments for ischemic stroke aim to achieve rapid reperfusion with intravenous thrombolysis and/or endovascular thrombectomy, which have proven to attenuate disability. Despite the significant progress in reperfusion therapies, functional recovery remains inconsistent, primarily due to ongoing neuronal excitotoxicity and neuroinflammation. In this study we investigated the relationship between neuronal activity and neuroinflammation in an ischemic mouse model using chemogenetic techniques. MCAO cerebral ischemia model was established in mice; in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) was established in PC12 neurons. By measuring c-Fos expression, we showed that MCAO caused the activation of both excitatory and inhibitory neurons within the M1 primary motor cortex, which subsequently induced reactive activation of local microglia through the secretion of unique neuronal extracellular vesicles (EVs). Chemogenetic inhibition of abnormal neuronal activity in stroke-affected cortical neurons reversed microglia activation and reduced neuronal apoptosis. By analyzing the miRNAs in EVs from the ischemic M1 cortex, we found that miR-128-3p was significantly downregulated in ischemia-challenged neurons and their EVs, leading to neuronal injury and proinflammatory polarization of microglia. Intravenous injection of miR-128-3p mimics significantly improved neuronal survival, reduced neuroinflammation accompanied by better functional recovery after ischemic stroke. In summary, stroke-induced abnormal neuronal activity reduces miR-128-3p levels in ischemic neurons and EVs, leading to increased microglia activation and neuronal injury after a stroke. The study highlights that inhibiting abnormal neuronal activity or delivering miR-128-3p-enriched EVs as novel methods for stroke treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2105-2119"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612923","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":"Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.","authors":"Chen Hu, Cong-Hua Lu, Jie Zheng, Jun Kang, Dai-Juan Huang, Chao He, Yi-Hui Liu, Zhan-Rui Liu, Di Wu, Yuan-Yao Dou, Yi-Min Zhang, Cai-Yu Lin, Rui Han, Yong He","doi":"10.1038/s41401-025-01511-z","DOIUrl":"10.1038/s41401-025-01511-z","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard treatments for EML4-ALK-positive NSCLC, but resistance to these agents remains a challenge. This study aimed to determine the mechanisms of acquired resistance to the third-generation ALK-TKI lorlatinib. Lorlatinib-resistant cell lines were established by prolonged exposure to a high concentration of lorlatinib. Activation of epidermal growth factor receptor (EGFR) caused by a decrease in endocytosis and degradation of protein was demonstrated to play an essential role in acquired resistance to lorlatinib. The interaction between the EGFR and ALK was investigated to identify binding sites and conformational changes in ALK. We performed high-throughput compound screening using a small-molecule drugs library comprising 510 antitumor agents in an effort to discover small-molecule compounds that target EGFR in lorlatinib-resistant cells. Combination treatment with ALK-TKI and anti-EGFR agents suppressed acquired resistance to ALK-TKIs caused by activation of EGFR in vitro and in vivo, suggesting that the combination of lorlatinib and an anti-EGFR agent could be effective in patients with lorlatinib-resistant NSCLC. This research provides insights into the mechanism of resistance to lorlatinib and suggests that it can be overcome by anti-EGFR treatment, offering a promising approach for treating resistance to lorlatinib mediated by EGFR activation in patients with ALK-positive NSCLC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2267-2281"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676780","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":"KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis.","authors":"Zhuo Wang, Yang Yang, Fang-Ting Yao, Feng Zhang, Ke-Ying Lin, Hong-Tao Diao, Qiao-Yue Zhao, Xue Kong, Wei Si, Ya-Ting Xie, Jing-Lun Song, Ling-Hua Zeng, Chun-Lei Wang, Yu-Ting Xiong, Kun-Kun Zou, Xiao-Man Wang, Xin-Yue Zhang, Han Wu, Wei-Tao Jiang, Yu Bian, Bao-Feng Yang","doi":"10.1038/s41401-025-01528-4","DOIUrl":"10.1038/s41401-025-01528-4","url":null,"abstract":"<p><p>Liver cancer is a highly aggressive malignancy with poor survival rates. Current treatments, including liver transplantation, immunotherapy, and gene therapy, are often limited by late-stage diagnosis and significant side effects, highlighting the urgent need for novel therapeutic agents. In this study, we evaluated the therapeutic potential of Kanglexin (KLX), a novel anthraquinone derivative, in the treatment of liver cancer. In vitro, KLX inhibited the proliferation and migration of HepG2 and Hep3B cells in a dose-dependent manner. Mechanistically, KLX upregulated Z-DNA binding protein 1 (ZBP1) expression, inducing PANoptosis by directly binding to ZBP1, altering its conformation, and reducing its affinity for the E3 ubiquitin ligase ring finger protein 180 (RNF180). This interaction decreased ZBP1 ubiquitination, thereby increasing its stability. Additionally, KLX upregulated the expression of the transcription factor homeobox D10 (HOXD10), which further increased ZBP1 expression. Elevated ZBP1 levels significantly suppressed liver cancer cell proliferation and migration, whereas the inhibitory effects of KLX were reversed upon ZBP1 knockdown. In a xenograft model, KLX significantly inhibited tumor growth with a lower toxicity than oxaliplatin (OXA). In conclusion, KLX promoted PANoptosis in liver cancer cells by upregulating ZBP1 and preventing its degradation, thereby inhibiting liver cancer progression and migration. These findings suggest that KLX is a promising therapeutic agent for liver cancer.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2282-2295"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727159","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":"Targeting cholesterol metabolism: a promising therapy strategy for cancer.","authors":"Chun-Lan Dai, Zi-Yang Qiu, An-Qi Wang, Shen Yan, Li-Jun Zhang, Xin Luan","doi":"10.1038/s41401-025-01531-9","DOIUrl":"10.1038/s41401-025-01531-9","url":null,"abstract":"<p><p>Cholesterol is a crucial structural component of cell membranes, playing a vital role in maintaining membrane fluidity and stability. Cholesterol metabolism involves four interconnected processes: de novo synthesis, uptake, efflux, and esterification. Disruptions in any of these pathways can lead to imbalances in cholesterol homeostasis, which are significantly associated with cancer progression. In recent years, traditional Chinese medicine (TCM) has emerged as a comprehensive therapeutic approach with multi-target and multi-pathway effects, demonstrating significant potential in regulating cholesterol metabolism. Research has shown that certain components of TCM can modulate enzymes, transport proteins, and signaling pathways involved in cholesterol metabolism, effectively interfering with survival and migration of cancer. These mechanisms highlight the unique advantages of TCM in inhibiting tumor progression. In this review we systematically describe the execution and regulation of the four key cholesterol metabolism processes, highlights the roles of critical proteins involved, and provides a comprehensive overview of natural products from TCM that modulate cholesterol metabolism. This review provides valuable insights for the development of novel drugs and cancer therapeutic strategies targeting cholesterol metabolism.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2093-2104"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708030","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":"MMP-9 inhibitor SB-3CT improves neurological outcomes in ischemic stroke mice by modulation of astrocytic lipid metabolism.","authors":"Li-da Du, Cheng Fang, Yue-Qing Wang, Zi-Ying Feng, Ogunleye Femi Abiola, Zhao-Lin Gao, Ju-Yang Huang, Yin-Zhong Ma","doi":"10.1038/s41401-025-01505-x","DOIUrl":"10.1038/s41401-025-01505-x","url":null,"abstract":"<p><p>The acute phase of ischemic stroke is marked by a surge in matrix metalloproteinase-9 (MMP-9) activity. While integral to natural repair processes, MMP-9 exacerbates injury by breaking down the blood-brain barrier (BBB) and promoting edema and inflammation. MMP-9 is predominantly secreted by inflammatory cells such as neutrophils, macrophages and microglia soon after stroke onset. In this study we investigated the effects of MMP-9 inhibition via SB-3CT on astrocytic lipid metabolism, and its potential to enhance neuronal survival and recovery following ischemic stroke. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, mice then were injected with SB-3CT (25 mg/kg, i.v.). On D3 post tMCAO, neurological outcomes were assessed, and whole brains were collected for analysis. Lipidomic analysis of brain tissue showed that SB-3CT treatment significantly restrained astrocytic cholesterol metabolism by modulating the sphingolipid and glycerophospholipid pathways. Specifically, SB-3CT reduced ceramide accumulation and promoted an increase in neuroprotective hexosylceramides, leading to enhanced neuronal survival and synaptic integrity. In addition, SB-3CT treatment reduced astrocytic and microglial reactivity, thereby mitigating neuroinflammation. In order to optimize the timing and dosage of MMP-9 inhibition to maximize the therapeutic efficacy, tMCAO mice were given three injections of SB-3CT on D0, D2 and D4 within 7 days after modeling. We found that prolonged MMP-9 inhibition alleviated astrogliosis, concurrently impaired neurological recovery and inhibited angiogenesis. These results demonstrate the critical role of lipid metabolism in MMP-9-mediated brain injury and the potential of SB-3CT as a therapeutic strategy for ischemic stroke by targeting astrocytic lipid metabolism.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2120-2135"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603179","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":"Genetic and pharmacological targeting of Snail inhibits atherosclerosis by relieving intraplaque endothelium dysfunction and associated inflammation.","authors":"Bo-Xue Ren, Zhao-Lan Zeng, Li Deng, Jia-Meng Hu, Ming-Zhen Chen, Hao-Wei Jiang, Chen-Zi Zang, Shen-Tong Fang, Stephen J Weiss, Jie Liu, Rong Fu, Zhao-Qiu Wu","doi":"10.1038/s41401-025-01519-5","DOIUrl":"10.1038/s41401-025-01519-5","url":null,"abstract":"<p><p>The intraplaque endothelium dysfunction and associated inflammation contribute to the progression of atherosclerosis. We previously show that zinc-finger transcription factor Snail is predominantly expressed in embryonic vascular endothelial cells (ECs), and deletion of Snail in ECs induces severe defects in vascular development and thus causes embryonic lethality. Snail is essentially absent at postnatal stage, and inducible deletion of Snail in ECs has no impact on physiological angiogenesis in postnatally developing or adult mice. In this study we investigated whether Snail was reactivated in vascular ECs during pathologically angiogenic process (e.g. the formation of atherosclerotic plaque) or could play a functional role in atherosclerosis progression. We showed that the expression levels of Snail were significantly elevated in ECs of human and mouse atherosclerotic plaques, and associated with the disease severity. In the accelerated and canonical mouse models of atherosclerosis, tamoxifen-inducible, EC-specific Snail deletion significantly reduced intraplaque endothelial dysfunction, inflammation and lipid uptake accompanied by enhanced plaque stability. By conducting scRNA-sequencing in ECs of ApoE^-/-Snail^iΔEC versus ApoE^-/-Snail^fl/fl arterial vessels, we demonstrated that Snail deletion significantly decreased histone acetylation on Ccl5 and Cxcl10 promoters, thereby decreased CCL5/CXCL10-driven vascular damage and inflammation. Administration with recombinant CXCL10 protein (2 μg/kg, i.v., once per week for three weeks) efficiently restored atherosclerosis in EC-specific Snail-deleted mice. Finally, we developed an orally bioavailable small-molecule Snail inhibitor LFW273 that displayed potent anti-atherosclerotic effects in mice. These results reveal Snail as a promising therapeutic target in atherosclerotic disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2196-2212"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708027","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":"Microemulsion-based drug delivery system identifies pepper alkaloids as anti-obesity compounds.","authors":"Tian-Kai Meng, Ruo-Lei Han, Peng Ma, Shu-Xin Chen, Bo-Han Qi, Zi-Xuan Wang, Xiao-Yu Li, Han-Song Deng","doi":"10.1038/s41401-025-01521-x","DOIUrl":"10.1038/s41401-025-01521-x","url":null,"abstract":"<p><p>Obesity is a significant contributor to various metabolic diseases such as heart disease and diabetes. Due to the adverse effects of synthetic anti-obesity drugs, natural products from functional food plants, which mimic the effects of synthetic chemicals, present promising alternatives. However, many natural plant-derived compounds are poorly soluble in water, resulting in low bioavailability within the gastrointestinal tract, a key limitation for the effectiveness of many hydrophobic substances. In this study we developed a microemulsion-based drug delivery system in Drosophila, which effectively enhanced the solubility of hydrophobic compounds without noticeable effects on food intake or survival in fruit flies. This system consisted of cremophor EL, ethanol and ethyl oleate (7:6:1), which enabled the establishment of an emulsion-based liquid high-fat diet (LHFD) model, followed by a pilot screening of 161 standard substances from traditional Chinese medicine. We found that piperine (PIP), an alkaloid derived from black pepper, significantly decreased triacylglycerol (TAG) levels in both the intestine and in whole flies. We demonstrated that piperine (1 mg/ml) significantly elevated cytosolic Ca²⁺ levels in enterocytes by activating Transient receptor potential (TRP) channels. TRPV1 agonists such as capsaicin and evodiamine (another alkaloid identified during the screening) also exhibited anti-obesity effects. Increased Ca²⁺ levels resulted in the suppression of dietary lipase Magro expression through the activation of the transcription factor cAMP response element binding protein (CREB). Furthermore, hydrophobic compounds in the microemulsion were successfully delivered to distal tissues including liver and brain blood vessels in mice, and PIP in the microemulsion was sufficient to reduce body weight in mice. In conclusion, we have developed a microemulsion-based U-GLAD platform for drug delivery, and piperine is identified as a weight-controlling compound, providing a novel approach to the treatment of obesity and its associated symptoms.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2310-2322"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668646","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}