Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.
{"title":"Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells","authors":"Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li","doi":"10.1016/j.phrs.2025.107643","DOIUrl":"10.1016/j.phrs.2025.107643","url":null,"abstract":"<div><div>Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107643"},"PeriodicalIF":9.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1016/j.phrs.2025.107642
Jiahao Wu , Kaihua Ji , Guangbo Kang , Manman Zhang , Jigang Wang , Lina Wang , Mengxue Gao , Xiaoxiao Jia , Xinran Lu , Yan Wang , Xinran Gao , Yufei Guo , Zhixin Zhu , Qinghua Wang , Zhenyu Zhao , Qiang Liu , He Huang
Radiotherapy is a method of treating cancer through radiation aimed at killing cancer cells or inhibiting their growth. However, radiotherapy has numerous side effects because it kills tumors while causing damage to normal cells or tissues. The literature shows that radiation can cause damage to heart tissue. This study found that engineered yeast that produced butyrate can maintain small intestinal barrier function by recovering GPR109A to reduce intestinal damage caused by abdominal irradiation in mice. We unexpectedly found that engineered yeast could mitigate irradiation-induced heart damage via the gut-heart axis. Mechanistically, engineered yeast enhanced taurine and nicotinamide metabolism by increasing the relative abundance of Akkermansia and Lachnospiraceae_NK4A136; then, yeast modulated cardiac function by activating the Sgcg and Nppa genes to attenuate cardiac damage induced by abdominal irradiation. Finally, we confirmed that engineered yeast mitigated cardiac damage caused by total body irradiation, which protected other vital organs through the intestinal tract. This study has a profound impact on cancer treatment, the emergence of engineered yeast will alleviate radiotherapy side effects and benefit patients.
{"title":"Butyrate-engineered yeast activates Nppa and Sgcg genes and reduces radiation-induced heart damage via the gut-heart axis","authors":"Jiahao Wu , Kaihua Ji , Guangbo Kang , Manman Zhang , Jigang Wang , Lina Wang , Mengxue Gao , Xiaoxiao Jia , Xinran Lu , Yan Wang , Xinran Gao , Yufei Guo , Zhixin Zhu , Qinghua Wang , Zhenyu Zhao , Qiang Liu , He Huang","doi":"10.1016/j.phrs.2025.107642","DOIUrl":"10.1016/j.phrs.2025.107642","url":null,"abstract":"<div><div>Radiotherapy is a method of treating cancer through radiation aimed at killing cancer cells or inhibiting their growth. However, radiotherapy has numerous side effects because it kills tumors while causing damage to normal cells or tissues. The literature shows that radiation can cause damage to heart tissue. This study found that engineered yeast that produced butyrate can maintain small intestinal barrier function by recovering GPR109A to reduce intestinal damage caused by abdominal irradiation in mice. We unexpectedly found that engineered yeast could mitigate irradiation-induced heart damage via the gut-heart axis. Mechanistically, engineered yeast enhanced taurine and nicotinamide metabolism by increasing the relative abundance of <em>Akkermansia</em> and <em>Lachnospiraceae_NK4A136</em>; then, yeast modulated cardiac function by activating the <em>Sgcg</em> and <em>Nppa</em> genes to attenuate cardiac damage induced by abdominal irradiation. Finally, we confirmed that engineered yeast mitigated cardiac damage caused by total body irradiation, which protected other vital organs through the intestinal tract. This study has a profound impact on cancer treatment, the emergence of engineered yeast will alleviate radiotherapy side effects and benefit patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107642"},"PeriodicalIF":9.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2024.107572
Lei Zhang, Yuqing Tian, Lingling Zhang, Huanyu Zhang, Jinghua Yang, Yi Wang, Na Lu, Wei Guo, Liang Wang
Syringaresinol, a phytochemical constituent belonging to lignan, is formed from two sinapyl alcohol units linked via a β-β linkage, which can be found in a wide variety of cereals and medicinal plants. Medical researches revealed that Syringaresinol possesses a broad spectrum of biological activities, including anti-inflammatory, anti-oxidation, anticancer, antibacterial, antiviral, neuroprotection, and vasodilation effects. These pharmacological properties lay the foundation for its use in treating various diseases such as inflammatory diseases, neurodegenerative disorders, diabetes and its complication, skin disorders, cancer, cardiovascular, and cerebrovascular diseases. As the demand for natural therapeutics increases, Syringaresinol has garnered significant attention for its pharmacological properties. Despite the extensive literature that highlights the various biological activities of this molecule, the underlying mechanisms and the interrelationships between these activities are rarely addressed from a comprehensive perspective. Moreover, no thorough comprehensive summary and evaluation of Syringaresinol has been conducted to offer recommendations for potential future clinical trials and therapeutic applications of this bioactive compound. Thus, a comprehensive review on Syringaresinol is essential to advance scientific understanding, assess its therapeutic applications, ensure safety, and guide future research efforts. This will ultimately contribute to its potential integration into clinical practice and public health. This study aims to provide a comprehensive overview of Syringaresinol on its sources and biological activities to provide insights into its therapeutic potential, and to provide a basis for high-quality studies to determine the clinical efficacy of this compound. Additionally, we explored the pharmacokinetics, toxicology, and drug development aspects of Syringaresinol to guide future research efforts. The review also discussed the limitations of current research on Syringaresinol and put forward some new perspectives and challenges, which laid a solid foundation for further study on clinical application and new drug development of Syringaresinol in the future.
{"title":"A comprehensive review on the plant sources, pharmacological activities and pharmacokinetic characteristics of Syringaresinol","authors":"Lei Zhang, Yuqing Tian, Lingling Zhang, Huanyu Zhang, Jinghua Yang, Yi Wang, Na Lu, Wei Guo, Liang Wang","doi":"10.1016/j.phrs.2024.107572","DOIUrl":"10.1016/j.phrs.2024.107572","url":null,"abstract":"<div><div>Syringaresinol, a phytochemical constituent belonging to lignan, is formed from two sinapyl alcohol units linked via a β-β linkage, which can be found in a wide variety of cereals and medicinal plants. Medical researches revealed that Syringaresinol possesses a broad spectrum of biological activities, including anti-inflammatory, anti-oxidation, anticancer, antibacterial, antiviral, neuroprotection, and vasodilation effects. These pharmacological properties lay the foundation for its use in treating various diseases such as inflammatory diseases, neurodegenerative disorders, diabetes and its complication, skin disorders, cancer, cardiovascular, and cerebrovascular diseases. As the demand for natural therapeutics increases, Syringaresinol has garnered significant attention for its pharmacological properties. Despite the extensive literature that highlights the various biological activities of this molecule, the underlying mechanisms and the interrelationships between these activities are rarely addressed from a comprehensive perspective. Moreover, no thorough comprehensive summary and evaluation of Syringaresinol has been conducted to offer recommendations for potential future clinical trials and therapeutic applications of this bioactive compound. Thus, a comprehensive review on Syringaresinol is essential to advance scientific understanding, assess its therapeutic applications, ensure safety, and guide future research efforts. This will ultimately contribute to its potential integration into clinical practice and public health. This study aims to provide a comprehensive overview of Syringaresinol on its sources and biological activities to provide insights into its therapeutic potential, and to provide a basis for high-quality studies to determine the clinical efficacy of this compound. Additionally, we explored the pharmacokinetics, toxicology, and drug development aspects of Syringaresinol to guide future research efforts. The review also discussed the limitations of current research on Syringaresinol and put forward some new perspectives and challenges, which laid a solid foundation for further study on clinical application and new drug development of Syringaresinol in the future.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107572"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2024.107571
Mingyu Wu , Ke Li , Jiabin Wu , Xianyi Ding , Xiaotong Ma , Wenhong Wang , Weihua Xiao
Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (Panax ginseng C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(S)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.
多种肝病具有诊断晚、进展快的特点，已成为威胁人类健康的主要疾病之一。为了延缓从良性组织病变到实质性器官损伤的转变，科学家们逐渐将植物中提取的天然化合物作为肝病学领域的补充疗法。人参（Panax Ginseng C. a . Meyer）是一种滋补的传统中草药，天然产物人参皂苷Rg1 （G-Rg1）是一种生物活性较高的20(S)-原人参三醇皂苷。鉴于这些信息，本文旨在总结和讨论G-Rg1在多种肝脏疾病调节中的代谢机制以及提高其生物利用度的措施。G-Rg1作为一种具有多靶点药理作用的中药单体，在缓解酒精性肝病、非酒精性脂肪性肝病、肝纤维化、病毒性肝炎等方面具有显著的治疗效果，其作用机制主要是通过抑制细胞凋亡、增强内源性抗炎抗氧化机制、激活免疫反应、调节外排转运信号等。改善肝脏因脂质沉积、炎症、氧化应激、肝毒性产物积累等引起的病理改变。但G-Rg1生物利用度差的问题必须克服，才能提高其临床应用价值。综上所述，关注G-Rg1的保肝作用将为开发针对肝脏疾病的天然中药资源及其药物提供新的思路。
{"title":"Ginsenoside Rg1: A bioactive therapeutic agent for diverse liver diseases","authors":"Mingyu Wu , Ke Li , Jiabin Wu , Xianyi Ding , Xiaotong Ma , Wenhong Wang , Weihua Xiao","doi":"10.1016/j.phrs.2024.107571","DOIUrl":"10.1016/j.phrs.2024.107571","url":null,"abstract":"<div><div>Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (<em>Panax ginseng</em> C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(<em>S</em>)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107571"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107597
Rebecca L. Brouillette , Christine E. Mona , Michael Desgagné , Malihe Hassanzedeh , Émile Breault , Frédérique Lussier , Karine Belleville , Jean-Michel Longpré , Michel Grandbois , Pierre-Luc Boudreault , Élie Besserer-Offroy , Philippe Sarret
β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET2-based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that depend on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP’s inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect in vivo, as intrathecal injection of ARIP potentiated morphine’s analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes.
{"title":"A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor","authors":"Rebecca L. Brouillette , Christine E. Mona , Michael Desgagné , Malihe Hassanzedeh , Émile Breault , Frédérique Lussier , Karine Belleville , Jean-Michel Longpré , Michel Grandbois , Pierre-Luc Boudreault , Élie Besserer-Offroy , Philippe Sarret","doi":"10.1016/j.phrs.2025.107597","DOIUrl":"10.1016/j.phrs.2025.107597","url":null,"abstract":"<div><div>β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET<sup>2</sup>-based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that depend on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP’s inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect <em>in vivo</em>, as intrathecal injection of ARIP potentiated morphine’s analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107597"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107592
Zhi-Ting Zhong , Xu-Yan Wang , Ying Pan , Ke Zhou , Jing-Hui Chen , Yu-Qi Gao , Bo Dai , Zhi-Ling Zhou , Rui-Qi Wang
Lung cancer (LC) is the leading cause of cancer-related morbidity and mortality in China, with non-small cell lung cancer (NSCLC) accounting for 85 % of the overall lung cancer cases. AMP-activated protein kinase (AMPK) is a key regulator of energy balance and homeostasis, and its dysregulation is a common feature in various malignancies, particularly in NSCLC with mutations in Liver kinase B1 (LKB1). Studies have shown that the AMPK signalling pathway has a dual role in NSCLC progression, both inhibiting and promoting the progression of malignant tumours. Therefore, drugs targeting the AMPK signalling pathway may hold significant promise for therapeutic application in NSCLC. This review aims to examine the manifestations and mechanisms by which AMPK and its associated signalling molecules influence NSCLC progression and treatment. Firstly, we discuss the critical importance of AMPK within the mutational context of NSCLC. Secondly, we summarise the drugs and related substances that modulate the AMPK signalling pathway in NSCLC and evaluate the evidence from preclinical studies on combination AMPK-targeted therapies to address the issue of drug resistance in NSCLC under current clinical treatments. In summary, this paper highlights the critical importance of developing AMPK-targeted drugs to enhance therapeutic efficacy in NSCLC, as well as the potential for applying these drugs in clinical therapy to overcome drug resistance.
{"title":"AMPK: An energy sensor for non-small cell lung cancer progression and treatment","authors":"Zhi-Ting Zhong , Xu-Yan Wang , Ying Pan , Ke Zhou , Jing-Hui Chen , Yu-Qi Gao , Bo Dai , Zhi-Ling Zhou , Rui-Qi Wang","doi":"10.1016/j.phrs.2025.107592","DOIUrl":"10.1016/j.phrs.2025.107592","url":null,"abstract":"<div><div>Lung cancer (LC) is the leading cause of cancer-related morbidity and mortality in China, with non-small cell lung cancer (NSCLC) accounting for 85 % of the overall lung cancer cases. AMP-activated protein kinase (AMPK) is a key regulator of energy balance and homeostasis, and its dysregulation is a common feature in various malignancies, particularly in NSCLC with mutations in Liver kinase B1 (LKB1). Studies have shown that the AMPK signalling pathway has a dual role in NSCLC progression, both inhibiting and promoting the progression of malignant tumours. Therefore, drugs targeting the AMPK signalling pathway may hold significant promise for therapeutic application in NSCLC. This review aims to examine the manifestations and mechanisms by which AMPK and its associated signalling molecules influence NSCLC progression and treatment. Firstly, we discuss the critical importance of AMPK within the mutational context of NSCLC. Secondly, we summarise the drugs and related substances that modulate the AMPK signalling pathway in NSCLC and evaluate the evidence from preclinical studies on combination AMPK-targeted therapies to address the issue of drug resistance in NSCLC under current clinical treatments. In summary, this paper highlights the critical importance of developing AMPK-targeted drugs to enhance therapeutic efficacy in NSCLC, as well as the potential for applying these drugs in clinical therapy to overcome drug resistance.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107592"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107599
Wang Xiang , Xiaolin Zhang , Minhai Dong , Lijun Wan , Bin Zhang , Feng Wan
Pediatric high-grade gliomas (pHGGs) are the most common brain malignancies in children and are characterized by blocked differentiation. The epigenetic landscape of pHGGs, particularly the H3K27-altered and H3G34-mutant subtypes, suggests these tumors may be particularly susceptible to strategies that target blocked differentiation. Differentiation therapy aims to overcome this differentiation blockade by promoting glioma cell differentiation into more mature and less malignant cells. Epigenetic modulators, including inhibitors of histone deacetylase (HDAC), enhancer of zeste homolog 2 (EZH2), BRG1/BRM-associated factor (BAF) complex, have shown promise in preclinical studies of pHGGs by altering the differentiation program of glioma cells. Although challenges remain in overcoming tumor cell heterogeneity, induced differentiation therapy holds promise for treating these currently incurable pediatric brain cancers.
{"title":"Differentiation therapy targeting the stalled epigenetic developmental programs in pediatric high-grade gliomas","authors":"Wang Xiang , Xiaolin Zhang , Minhai Dong , Lijun Wan , Bin Zhang , Feng Wan","doi":"10.1016/j.phrs.2025.107599","DOIUrl":"10.1016/j.phrs.2025.107599","url":null,"abstract":"<div><div>Pediatric high-grade gliomas (pHGGs) are the most common brain malignancies in children and are characterized by blocked differentiation. The epigenetic landscape of pHGGs, particularly the H3K27-altered and H3G34-mutant subtypes, suggests these tumors may be particularly susceptible to strategies that target blocked differentiation. Differentiation therapy aims to overcome this differentiation blockade by promoting glioma cell differentiation into more mature and less malignant cells. Epigenetic modulators, including inhibitors of histone deacetylase (HDAC), enhancer of zeste homolog 2 (EZH2), BRG1/BRM-associated factor (BAF) complex, have shown promise in preclinical studies of pHGGs by altering the differentiation program of glioma cells. Although challenges remain in overcoming tumor cell heterogeneity, induced differentiation therapy holds promise for treating these currently incurable pediatric brain cancers.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107599"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107614
Kuo-Jen Lin , I-Hung Shao , Yu-Hsiang Lin
{"title":"The interplay of aging, sleep dysregulation, and mitochondrial dysfunction in metabolic and neurodegenerative diseases","authors":"Kuo-Jen Lin , I-Hung Shao , Yu-Hsiang Lin","doi":"10.1016/j.phrs.2025.107614","DOIUrl":"10.1016/j.phrs.2025.107614","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107614"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2024.107569
Elena Cattaneo , Dario Besusso
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Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107576
Yanhua Zhao , Zhisheng Lu , Xuesong Song , Haihui Xie , Xungang Xiao , Guonian Wang , Qi Zhou , Qingmei Zhang , Liang Liu , Zhijian Lan , Ning Bai , Haiyan Wang , Zhihao Pan , Liang Dong , Xianzhong Lin , Gang Chen , Qinghui Wang , Jiangtao Dong , Jia Deng , Yongshan Nan , Xiyao Gu
Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID24). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and −19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery.
Trial Registration
Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.
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