Acta Pharmacologica Sinica最新文献

{"title":"Huperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission.","authors":"Yu Wang, Ke-Yu Hu, Qing-Yang Zhang, Ying-Jie Song, Ling-Jie Li, Fei Wang, Gang Tian, Fan Fei, Ceng-Lin Xu, Jia-Jia Fang, Xu-Hong Jiang, Jian-Nong Wu, Wen-Lu Li, Yi Wang, Zhong Chen","doi":"10.1038/s41401-025-01522-w","DOIUrl":"10.1038/s41401-025-01522-w","url":null,"abstract":"<p><p>Cholinergic transmission, independent of classical glutamatergic and GABAergic signaling, critically plays a crucial role in epilepsy. Huperzine A (Hup A), an acetylcholinesterase (AChE) inhibitor, exerts potent anticonvulsant activity, but its mechanism of action within cholinergic circuits remains unclear. Here, we show that Hup A mitigates epileptic seizures by enhancing hippocampal dorsal CA1 (dCA1)-projecting cholinergic transmission. We found that systemic injection of Hup A not only reduces seizures in acute models, including the maximal-electroshock seizure (MES), pentylenetetrazol (PTZ), and kainic acid (KA) models but also alleviates the seizure severity in chronic epilepsy models induced by kindling and KA, indicating a broad-spectrum anti-seizure efficacy. Interestingly, using immunohistochemistry, viral tracing, and in vivo fiber photometry, we found that Hup A selectively inhibits AChE in the dCA1 rather than in other hippocampal subregions or cortex, enhancing dCA1-projecting septal cholinergic transmission. Significantly, selective ablation of septal ChAT⁺ neurons reversed the anti-seizure effects of Hup A. We further identified that α7 nicotinic acetylcholine receptors in the dCA1 region mediate the anti-seizures cholinergic circuit modulated by Hup A. Together, our results demonstrate that Hup A exerts broad-spectrum anti-seizure efficacy via modulating dCA1-projecting septal cholinergic transmission, providing potential therapeutic avenues for epilepsy through targeted cholinergic modulation.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717613","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":"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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of calcium signaling in organotropic metastasis of cancer.","authors":"Yong-Hao Li, Chu-Run Zheng, Yue Liu, Ke Wang, Fan-Fan Zhou, Xin Dong, Tao Yuan, Qiao-Jun He, Hong Zhu, Bo Yang","doi":"10.1038/s41401-025-01537-3","DOIUrl":"10.1038/s41401-025-01537-3","url":null,"abstract":"<p><p>Tumor metastasis is an important event in cancer progression, representing an enduring and irrevocable hallmark of cancers. The causes of tumor metastasis are complex and diverse. Arising evidence shows that the dysregulation of calcium signaling plays a crucial role in its initiation and progress. Calcium is an essential secondary messenger that regulates signaling pathways associated with tumor metastasis. The transient accumulation of calcium potentially promotes the advancement of tumor metastasis, while calcium-dependent proteins and calcium-related channels also significantly contribute to such malignant process. Thus, compounds specially targeting calcium channels, transporters or pumps may be therapeutic approaches prohibiting tumor metastasis. This review focuses on exploring the roles of calcium ions, calcium-dependent proteins and calcium-related channels in organotropic metastasis of cancer and its clinical applications in the treatment of metastatic cancers.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708032","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 the HuR/E2F7 axis synergizes with bortezomib against multiple myeloma.","authors":"Ming-Yuan Jia, Chao Wu, Ze Fu, Wen-Bin Xu, Jia Liu, Cheng-Yu Wu, Xin-Yi Zeng, Ying-Li Wu, Hua Yan","doi":"10.1038/s41401-025-01529-3","DOIUrl":"10.1038/s41401-025-01529-3","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a malignant hematological disease caused by the proliferation of abnormal plasma cells in the bone marrow and is still incurable. Relapse and drug resistance are common in MM. New therapeutic targets are urgently needed for MM treatment. Human antigen R (HuR) has been reported to play an important role in the malignant biological behavior of a variety of tumors, but its role in MM remains unclear. In this study, we found that HuR was highly expressed in MM patients and associated with a poor prognosis by analyzing public datasets. We found that targeting HuR with short hairpin RNA (shRNA) or its inhibitor CMLD-2 had significant anti-MM effects both in vitro and in vivo. The overexpression of HuR promotes MM cell proliferation in vitro and in vivo. Moreover, we demonstrated that bortezomib drug sensitivity increased and decreased with the knockdown and overexpression of HuR, respectively. This result provides a rationale for our subsequent combination of CMLD-2 with bortezomib in the treatment of MM. To further explore the mechanism of HuR in MM, we performed RNA sequencing and identified its downstream molecule, E2F7. HuR upregulated E2F7 expression by increasing the stability of its mRNA in MM cells. Higher levels of E2F7 were associated with a poorer prognosis. E2F7 knockdown had anti-MM effects in vitro and in vivo. E2F7 overexpression partially rescued the cell proliferation inhibition and apoptosis caused by targeting HuR in MM cells. We subsequently demonstrated that CMLD-2 synergized with the anti-MM effect of bortezomib both in vitro and in vivo. In conclusion, targeting the HuR/E2F7 axis synergizes with bortezomib against MM. Therefore, the HuR/E2F7 axis may serve as a promising therapeutic target for MM.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708031","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":"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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.","authors":"Jia-Wen Xu, Lin Ma, Yu Xiang, Meng-Qing Dai, Qiu-Hui Li, Xiao-Yan Jin, Yuan Ruan, Yang Li, Jia-Ying Wang, Xu Shen","doi":"10.1038/s41401-025-01526-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01526-6","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC₅₀ value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg^-1·d^-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668628","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":"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":"https://doi.org/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":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}