Acta Pharmacologica Sinica最新文献_第9页

NOX1 inhibition sensitizes HCC cells to sorafenib and radiotherapy by modulating ROS-mediated programmed cell death. NOX1抑制通过调节ros介导的程序性细胞死亡使HCC细胞对索拉非尼和放疗增敏。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-07 DOI: 10.1038/s41401-025-01623-6

Wei Mu, Ya-Ge Shi, Yu-Lun Jian, Lei Li, Yan-Feng Zhou, Hui Wang, Yang Ge

{"title":"NOX1 inhibition sensitizes HCC cells to sorafenib and radiotherapy by modulating ROS-mediated programmed cell death.","authors":"Wei Mu, Ya-Ge Shi, Yu-Lun Jian, Lei Li, Yan-Feng Zhou, Hui Wang, Yang Ge","doi":"10.1038/s41401-025-01623-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01623-6","url":null,"abstract":"The progression of hepatocellular carcinoma (HCC) is partly driven by reactive oxygen species (ROS)-induced tissue damage and inflammation. Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are key regulators of ROS production, yet the specific role of NOX1 in HCC progression and therapeutic response remain incompletely understood. In this study we investigated the critical role of NOX1 in progression, metastasis and therapeutic sensitivity of HCC, and explored its potential as a therapeutic target. By comprehensive analysis of public databases and validation with in-house clinical specimens, we showed that NOX1 expression was significantly elevated in metastatic HCC that was correlated to poor patient prognosis. Knockdown of NOX1 or pharmacological inhibition with a selective NOX1 inhibitor ML171 significantly reduced ROS production and suppressed HCC cell motility and invasion in vitro. NOX1 inhibition also attenuated HCC metastasis in experimental metastasis mouse model using direct injection of HCC cells, and mitigated CCl4-induced liver injury and pro-tumorigenic microenvironment in CCl4-induced chronic liver injury and spontaneous tumor development mouse model. Importantly, we demonstrated that combined sorafenib or radiotherapy with NOX1 inhibition synergistically reduced the metastatic potential of HCC cells and enhanced the therapeutic efficacy. Bioinformatics analysis revealed that NOX1 contributed to HCC metastasis and therapy resistance by modulating ROS homeostasis, cellular antioxidant systems and inflammatory pathways. Taken together, this study elucidates the critical role of NOX1 in HCC pathogenesis, suggesting that NOX1 inhibition represents a promising strategy to overcome resistance and enhance HCC sensitivity to sorafenib and radiotherapy.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797933","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}

引用次数: 0

USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer. 在缺氧胁迫下，USP3通过去泛素化稳定MIC19，促进非小细胞肺癌的进展。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-06 DOI: 10.1038/s41401-025-01625-4

Wen-Hao Zhao, Hua Huang, Chen Ding, Ze-Xia Zhao, Chao-Yi Jia, Ying-Jie Wang, Zi-Xuan Hu, Guan-Nan Wang, Yong-Wen Li, Jing-Hao Liu, Hong-Yu Liu, Jun Chen

{"title":"USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer.","authors":"Wen-Hao Zhao, Hua Huang, Chen Ding, Ze-Xia Zhao, Chao-Yi Jia, Ying-Jie Wang, Zi-Xuan Hu, Guan-Nan Wang, Yong-Wen Li, Jing-Hao Liu, Hong-Yu Liu, Jun Chen","doi":"10.1038/s41401-025-01625-4","DOIUrl":"https://doi.org/10.1038/s41401-025-01625-4","url":null,"abstract":"Hypoxia is a common phenomenon in the microenvironment of solid tumors; mitochondria, as the site of cellular oxidative respiration, are among the first organelles to be affected under hypoxic conditions. Mitochondrial cristae organizing protein 19 (MIC19), a core component of the mitochondrial contact site and cristae organizing system (MICOS), is essential for preserving mitochondrial activity. In this study, we investigated the effects of hypoxia on MIC19 and its regulatory mechanisms in non-small cell lung cancer (NSCLC). We showed that the expression levels of MIC19 were significantly increased in NSCLC, which were associated with advanced stages and a poor prognosis in patients with NSCLC. We demonstrated that MIC19 promoted the proliferation and invasion of A549 and PC9 cells in vitro, and MIC19 played a crucial role in maintaining mitochondrial function. We revealed that USP3 mediated the hypoxia-induced upregulation of MIC19 expression in A549 and PC9 cells. In the hypoxic microenvironment, HIF-1α bound to the USP3 promoter region and promoted USP3 expression, which in turn stabilized MIC19 through K48-linked deubiquitination, thereby driving NSCLC progression. The role of MIC19 in NSCLC growth and progression was confirmed in nude mice bearing A549 xenograft tumors in vivo. In conclusion, under hypoxic conditions, USP3 stabilizes MIC19 through deubiquitination, thereby promoting NSCLC progression. This study reveals the HIF1α-USP3-MIC19 axis in NSCLC progression, providing a theoretical basis for future therapeutic strategies.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793200","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}

引用次数: 0

Betaine-homocysteine methyltransferase protects against acetaminophen-induced acute liver failure via BACH1-SCD1-oleic acid axis. 甜菜碱-同型半胱氨酸甲基转移酶通过bach1 - scd1 -油酸轴保护对乙酰氨基酚诱导的急性肝衰竭。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-05 DOI: 10.1038/s41401-025-01622-7

Yu-Ting Zhang, Xiao-Ming Yang, Quan-Shan Jin, Jia-Yi Chen, Nan-Bin Zhu, Yi Ju, Zi-Yan Lin, Yang Zhi, Yi-Nuo Dong, Chun-Min Li, Yi-Min Mao, Xiu-Ling Zhi, Ming-Yang Ma, Ya-Li Xu, Xiao-Bo Li

{"title":"Betaine-homocysteine methyltransferase protects against acetaminophen-induced acute liver failure via BACH1-SCD1-oleic acid axis.","authors":"Yu-Ting Zhang, Xiao-Ming Yang, Quan-Shan Jin, Jia-Yi Chen, Nan-Bin Zhu, Yi Ju, Zi-Yan Lin, Yang Zhi, Yi-Nuo Dong, Chun-Min Li, Yi-Min Mao, Xiu-Ling Zhi, Ming-Yang Ma, Ya-Li Xu, Xiao-Bo Li","doi":"10.1038/s41401-025-01622-7","DOIUrl":"10.1038/s41401-025-01622-7","url":null,"abstract":"Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure, with limited preventive or therapeutic options. The role of betaine-homocysteine methyltransferase (BHMT), a key enzyme in the methionine cycle, remains unclear. We found that BHMT, primarily expressed in hepatocytes, showed reduced expression in the liver but elevated serum levels in the APAP-induced liver injury (AILI) mouse model. GalNAc-mediated targeted knockdown of Bhmt in hepatocytes aggravated AILI in mice. Through RNA-seq screening, we found that Bhmt deficiency dramatically suppressed stearoyl-coenzyme A desaturase 1 (SCD1) expression. Knockdown of Scd1 also exacerbated AILI. Mechanistically, Bhmt knockdown decreased the DNA methylation of BACH1 (BTB and CNC homology 1), a transcriptional factor, leading to upregulated BACH1 expression in primary mouse hepatocytes (PMHs) treated with APAP. BACH1 then bound to the enhancer region of Scd1, transcriptionally repressing SCD1. Lipidomic analysis revealed that Bhmt or Scd1 deficiency reduced levels of intracellular unsaturated fatty acids, particularly oleic acid (OA), whereas SCD1 overexpression increased OA levels and decreased lipid peroxides. OA administration alleviated AILI and mitigated the hepatotoxicity associated with Bhmt or Scd1 knockdown. Our findings indicate that BHMT mitigates AILI via the BACH1-SCD1-OA axis, suggesting that BHMT could serve as a preventive target for AILI, while increasing OA intake may offer dietary benefits for patients.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787965","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}

引用次数: 0

Transport mechanism and drug discovery of human monocarboxylate transporter 1. 人单羧酸转运蛋白的转运机制及药物发现

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-17 DOI: 10.1038/s41401-025-01517-7

Sai Shi, Jia-Chen Li, Xiao-Yu Zhou, Zhen-Lu Li, Ya-Xin Wang, Bing-Hong Xu, Sheng Ye

{"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":"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.","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}

引用次数: 0

Hepatocyte cellular repressor of E1A-stimulated genes 1 protects against acetaminophen-induced liver injury by promoting autophagy. e1a刺激基因1的肝细胞抑制因子通过促进自噬来保护对乙酰氨基酚诱导的肝损伤。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-25 DOI: 10.1038/s41401-025-01532-8

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

{"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":"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 Creg1fl/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 Creg1Δhep 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.","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}

引用次数: 0

CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate TLR4/NF-κB/ROS signaling. 来自SARS-CoV-2的CircSARS-CV2-N1368通过上调ATF7激活TLR4/NF-κB/ROS信号通路，损害内皮细胞功能。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-11 DOI: 10.1038/s41401-025-01516-8

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

{"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":"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.","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}

引用次数: 0

Aberrant neuronal excitation promotes neuroinflammation in the primary motor cortex of ischemic stroke mice. 异常神经元兴奋促进缺血性脑卒中小鼠初级运动皮层的神经炎症。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-12 DOI: 10.1038/s41401-025-01518-6

Ting-Ting Li, Xiao-Fan Guo, Yi-Jing Zhao, Ya-Hong Cheng, Dan-Qing Xin, Yan Song, De-Xiang Liu, Zhen Wang

{"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":"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.","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}

引用次数: 0

Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR. 抗表皮生长因子受体（EGFR）疗法可以克服第三代ALK-酪氨酸激酶抑制剂lorlatinib因表皮生长因子受体激活而产生的获得性耐药性。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-21 DOI: 10.1038/s41401-025-01511-z

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

{"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":"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.","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}

引用次数: 0

KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis. KLX通过介导ZBP1的转录和泛素化以及增加ZBP1诱导的PANoptosis来改善肝癌的进展。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-27 DOI: 10.1038/s41401-025-01528-4

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

{"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":"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.","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}

引用次数: 0

Targeting cholesterol metabolism: a promising therapy strategy for cancer. 靶向胆固醇代谢：一种有前途的癌症治疗策略。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-08-01 Epub Date: 2025-03-25 DOI: 10.1038/s41401-025-01531-9

Chun-Lan Dai, Zi-Yang Qiu, An-Qi Wang, Shen Yan, Li-Jun Zhang, Xin Luan

{"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":"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.","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}

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