Acta Pharmacologica Sinica最新文献

{"title":"Selective recognition memory impairment in mitochondrial hydroxylase Clk1 mutant mice, rescued by antipsychotics.","authors":"Zhi-Feng Shi, Zhe-Xiang Yu, Ling-Han Gu, Zhi-Xue Ma, Qin-Bo Chen, Li-Bin Wen, John L Waddington, Xue-Chu Zhen","doi":"10.1038/s41401-025-01641-4","DOIUrl":"10.1038/s41401-025-01641-4","url":null,"abstract":"<p><p>Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1^+/- mutant mice are resistant to morphine- and methamphetamine-induced conditioned place preference. Given the critical role of learning and memory in drug dependence, we herein explored whether and how Clk1 deficiency affected the cognitive processes in mice. We found that mutant Clk1 mice (Clk1^+/-) exhibited recognition memory impairment in novel object recognition (NOR) and novel arm recognition (NAR) tests. In addition, we observed in Clk1^+/- mutant mice a selective reduction in dendritic spine density in prefrontal cortex (PFC) but not in the hippocampus (HIP). The expression of brain-derived neurotrophic factor (BDNF) was also decreased in PFC but not in HIP. Furthermore, Clk1^+/- mutant mice displayed impairment in the ERK/CREB signaling pathway in PFC that might underlie Clk1^+/- mutation-induced changes in BDNF and dendritic morphology. Administration of antipsychotic drugs aripiprazole (0.3 mg·kg^-1·d^-1, i.p.) or risperidone (1 mg·kg^-1·d^-1, i.p.) for 7 days fully rescued Clk1 mutation-induced recognition memory deficits. This study provides primary evidence highlighting the role of mitochondrial Clk1 in the regulation of recognition memory and presents an informative model for investigating mitochondrial function in learning and memory.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938372","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":"NSCLC cells sustain phase separation of cytoplasmic membrane-less organelles to protect themselves against cisplatin treatment.","authors":"Ning-Ning Li, Ling-Ling Rao, Dan Su, Bin-Hao Liu, Guo-Qiang Ma, Hong-Feng Wang, Zeng-Li Zhang, Zheng Ying","doi":"10.1038/s41401-025-01551-5","DOIUrl":"10.1038/s41401-025-01551-5","url":null,"abstract":"<p><p>Cisplatin is the first platinum compound used for anticancer therapy, including non-small cell lung cancer (NSCLC). However, the clinical efficacy of cisplatin is strongly limited by cisplatin resistance. Hence, illuminating the mechanism of cisplatin resistance will aid in the development of therapeutic strategies that improve the sensitivity of cancer cells to cisplatin. Interestingly, membrane-less organelles, which are formed through biomolecular condensation in association with phase separation, have been recently linked with cancers. Here, we reveal a new molecular basis of cisplatin resistance in NSCLC, showing that cisplatin kills cancer cells by the alteration of cytoplasmic membrane-less organelles. Specifically, cisplatin treatment results in the disassembly of processing bodies (PBs) and the assembly of stress granule (SG)-like granules which are different from canonical SGs in NSCLC cells, but not cisplatin-resistant NSCLC cells. Moreover, alterations of PBs and noncanonical SG-like granules are associated with cisplatin-induced cancer cell death. Importantly, we found that disrupting PBs and canonical SGs with cycloheximide and FDA-approved pyrvinium helps cisplatin to kill cisplatin-resistant NSCLC cells. Taken together, our findings provide insight into the role of membrane-less organelle regulation in cisplatin resistance and offer an effective solution for overcoming cisplatin resistance in NSCLC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2522-2533"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957776","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":"Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC.","authors":"Jie Wang, Cui Zhang, Jia Qin, Ning An, Mei Bai, Rong-Hui Du, Yan Shen, Xu-Dong Wu, Jing-Cai Cheng, Xue-Feng Wu, Qiang Xu","doi":"10.1038/s41401-025-01549-z","DOIUrl":"10.1038/s41401-025-01549-z","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20 mg·kg^-1·d^-1, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5 µM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2436-2449"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802221","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":"Nicotine promotes the progression and metastasis of non-small cell lung cancer by modulating the OTUB1-c-Myc-EZH2 axis.","authors":"Hua Huang, Chen Ding, Wen-Hao Zhao, Hong-Bing Zhang, Ze-Xia Zhao, Xuan-Guang Li, Ying-Jie Wang, Pei-Jie Chen, Bo-Shi Li, Xue-Bing Li, Yong-Wen Li, Hong-Yu Liu, Jun Chen","doi":"10.1038/s41401-025-01527-5","DOIUrl":"10.1038/s41401-025-01527-5","url":null,"abstract":"<p><p>Smoking has been identified as a major risk factor for the development and progression of non-small cell lung cancer (NSCLC). As a key component of tobacco smoke, nicotine is believed to play a significant role in promoting NSCLC growth and progression. EZH2 is an epigenetic regulator highly expressed in the tumor tissues of smokers. However, whether and how nicotine regulates the expression of EZH2 and the underlying mechanisms remain unclear. Bioinformatics analysis and immunohistochemistry were used to compare the expression of EZH2 in NSCLC samples between smokers and nonsmokers. Western blotting, real-time quantitative PCR, and immunofluorescence were employed to confirm the effects of nicotine on EZH2 expression. Cell Counting Kit-8 assays, colony formation assays, 5-ethynyl-2-deoxyuridine staining, and Transwell assays were conducted to analyze the proliferation and metastasis of A549 and H1650 cells treated with siRNA or EZH2 inhibitors. Real-time quantitative PCR and chromatin immunoprecipitation assays were performed to assess the regulatory effect of nicotine on EZH2 transcript levels via c-Myc. Coimmunoprecipitation and ubiquitination assays were used to assess the deubiquitination of c-Myc by OTUB1. Finally, a nude mouse model was used to evaluate the impact of combined c-Myc and EZH2 inhibitors on tumor proliferation and metastasis in vivo. EZH2 is expressed at relatively high levels in NSCLC patients, as determined by both bioinformatic and IHC analyses. Nicotine upregulates EZH2 expression and promotes the proliferation and metastatic ability of lung cancer cells. Inhibition of EZH2 with either DZNep or EPZ6438, EZH2 inhibitors, or siRNA significantly decreased the proliferative and metastatic capacity of NSCLC cells induced by nicotine treatment. Moreover, the study revealed that nicotine induces OTUB1 expression, stabilizes the c-Myc protein via deubiquitination, and enables c-Myc-mediated transcriptional activation of EZH2. Furthermore, the c-Myc inhibitor 10058-F4 exhibited synergistic effects with the EZH2 inhibitor DZNep in suppressing NSCLC cell proliferation and metastasis both in vitro and in vivo.Nicotine regulates the c-Myc/EZH2 signaling pathway via OTUB1-mediated deubiquitination, thereby promoting the proliferation and metastasis of NSCLC cells. This research reveals novel molecular mechanisms of nicotine in the development of NSCLC, providing a theoretical foundation for future therapeutic strategies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2509-2521"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762637","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":"Identification of indoles as potential endogenous ligands of ERRγ and their modulation on drug binding.","authors":"Yuan-Yuan Shuai, Hong-Yang Zhang, Rui Chen, Bai-Ling Wang, Ping Ding, Yan Dong, Ming-Ze Sun, Xi-Shan Wu, Yong Xu, Yan Zhang, Jin-Song Liu, Na Wang, Ting-Ting Xu","doi":"10.1038/s41401-025-01550-6","DOIUrl":"10.1038/s41401-025-01550-6","url":null,"abstract":"<p><p>Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor in the ERR subfamily that plays a crucial role in regulating energy metabolism. To date, no endogenous ligand has been identified for ERRγ, posing a challenge for developing targeted therapeutics. Here, we identified that indole and skatole produced by the gut microbiota are potential endogenous ligands of ERRγ using biochemical, cellular, structural, and computational approaches. Indole and skatole increased ERRγ thermostability and directly bound to the ligand-binding domain (LBD) with a K_d of approximately 1-2 μM but had no significant effect or weak inhibitory activity on the transcriptional efficiency. However, RNA sequencing revealed that ERRγ could coregulate several lipid metabolism- and immune-related genes with indole, suggesting a role for ERRγ in the indole pathway. Interestingly, indole and skatole differentially attenuated the activities of ERRγ ligands: they both neutralized the agonistic activity of GSK4716, while indole reduced the antagonistic activity of 4-hydroxytamoxifen (4OHT) and GSK5182, and skatole affected the agonistic activity of endocrine disruptor bisphenol A (BPA). We further screened additional indole metabolites and analogs, resolved the complex structures of ERRγ-LBD with these compounds, and conducted molecular dynamics simulations to determine their binding site and elucidate their binding mechanisms. This study identified potential endogenous ligands of ERRγ, suggesting a novel link between the energy metabolism regulation and the indole pathway. Our findings highlight the need to consider endogenous ligands when designing and optimizing ERRγ-targeted drugs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2574-2582"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810168","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":"Complexin 2 contributes to the protective effect of NAD⁺ on neuronal survival following neonatal hypoxia-ischemia.","authors":"Xiao-Wen Xu, Xiu-Wen Zhou, Li Zhang, Qing Wang, Xin-Xin Wang, Yi-Ming Jin, Li-Li Li, Mei-Fang Jin, Hai-Ying Wu, Xin Ding, Hong Ni","doi":"10.1038/s41401-025-01555-1","DOIUrl":"10.1038/s41401-025-01555-1","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in cell metabolism associated with aging, cancer, neurodegenerative diseases and metabolic disorders. We recently showed that NAD⁺ therapy significantly improved neurobehavioral outcomes in neonatal mice after hypoxia-ischemia (HI), and bioinformatics analysis revealed that the expression of complexin 2 (CPLX2) in the injured cerebral cortex was significantly decreased 24 h after HI injury but could be reversed by NAD⁺ intervention. In this study we explored the role of CPLX2 in the survival and function of neonatal hypoxic-ischemic cortical neurons. HI models were established by permanent ligation of the left common carotid artery in mice. CPLX2-knockdown lentiviral vector was injected intraventricularly on postnatal day 1 (P1); CPLX2 knockout mice were also used. NAD⁺ (5 mg·kg^-1·d^-1, i.p.) was administered before HI surgery, thereafter once a day until sampling. We showed that NAD⁺ administration significantly ameliorated the morphological damages and neurobehavioral defects, and elevated the seizure thresholds in HI mice. All the beneficial effects of NAD⁺ were abolished by CPLX2 knockdown or knockout. In HT22 neuronal cells subjected to OGD/R, pretreated with NAD⁺ (100 μM) for 12 h significantly increased the cell viability, decreased the LDH levels, and inhibited the ferroptosis evidenced by the changes in redox-related parameters including concentrations of Fe²⁺, GSH, MDA, H₂O₂ as well as the expression of GPX4 and SLC7A11. CPLX2 knockdown in HT22 neuronal cells blocked the protective effects of NAD⁺ as in HI mice, whereas CPLX2 overexpression enhanced the inhibitory effects of NAD⁺ on ferroptosis in HT22 neuronal cells.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2363-2375"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962202","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":"Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors.","authors":"San-Shan Jin, Heng Zhang, Jia-Hui Yan, Can-Rong Wu, Xiao-Qing Cai, Kai Wu, Ming-Wei Wang, H Eric Xu, De-Hua Yang, Yi Jiang","doi":"10.1038/s41401-025-01633-4","DOIUrl":"https://doi.org/10.1038/s41401-025-01633-4","url":null,"abstract":"<p><p>Histamine H3 receptor (H3R) and H4 receptor (H4R) are key members of the histamine receptor family, with H3R as a potential target for narcolepsy treatments and H4R as a candidate for next-generation antihistamines for inflammatory and allergic diseases. Although progress has been made in understanding the structure of histamine receptors, the detailed mechanisms of ligand recognition and receptor antagonism for H3R and H4R remain unclear. In this study, using cryo-electron microscopy, we present an inactive structure of H4R bound to a selective antagonist, adriforant, and two Gi-coupled structures of H3R and H4R in complex with histamine. Our structural and mutagenesis analyses provide insights into the selective binding of adriforant to H4R and the recognition of histamine across histamine receptors. Our findings also uncovered distinct antagonistic mechanisms for H3R and H4R and identified the role of aromatic amino acids on extracellular loop 2 in modulating the constitutive activity of H3R and H4R. These findings advance our knowledge of the functional modulation of histamine receptors, providing a foundation for the development of targeted therapeutics for neurological and immune-related disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938341","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":"AI-enhanced virtual screening approach to hit identification for GluN1/GluN3A NMDA receptor.","authors":"Yue-Shan Ji, Yue Zeng, Shao-Fei Hu, Shu-Wang Li, Bei-Chen Zhang, Chang Liu, Hao-Chen Wu, An-Yang Wang, Zhao-Bing Gao, Yue Kong","doi":"10.1038/s41401-025-01644-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01644-1","url":null,"abstract":"<p><p>N-methyl-D-aspartate receptors (NMDARs) are calcium-permeable ionotropic glutamate receptors broadly expressed throughout the central nervous system, where they play crucial roles in neuronal development and synaptic plasticity. Among the various subtypes, the GluN1/GluN3A receptor represents a unique glycine-gated NMDAR with notably low calcium permeability. Despite its distinctive properties, GluN1/GluN3A remains understudied, particularly with respect to pharmacological tools development. This scarcity poses challenges for deeper investigation into its physiological functions and therapeutic relevance. In this study, we employed a hybrid virtual screening (VS) pipeline that integrates ligand-based and structure-based approaches for the efficient and precise identification of small-molecule candidates targeting GluN1/GluN3A. A large compound library comprising 18 million molecules was screened using an AI-enhanced multi-stage method. The initial phase utilized shape similarity ranking via ROCS-BART, followed by refinement with a graph neural network (GNN)-based drug-target interaction model to enhance docking accuracy. Functional validation using calcium flux (FDSS/μCell) identified two compounds with IC₅₀ values below 10 μM. Of these, one candidate exhibited potent inhibitory activity with an IC₅₀ of 5.31 ± 1.65 μM, which was further confirmed through manual patch-clamp recordings. These findings highlight an AI-enhanced VS workflow that achieves both efficiency and precision, providing a promising framework for exploring elusive targets such as GluN1/GluN3A.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938321","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":"Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.","authors":"Yi-Min Gu, Qing-Ning Yuan, Xin Li, Qian He, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41401-025-01635-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01635-2","url":null,"abstract":"<p><p>The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), functioning as a dual amylin receptor (AMYRs) and calcitonin receptor (CTR) agonist (DACRA), demonstrates significant efficacy in obesity treatment, although its structural activation mechanism remains unclear. This study elucidates the non-selective activation mechanism by determining cryo-EM structures of Cagri bound to AMY₁R-G_s and CTR-G_s complexes. Cagri adopts similar \"bypass\" binding modes in both receptors, which is distinct from other existing DACRAs that primarily achieve extended half-life through N-terminal lipid modification. Key molecular features include the F23^Cagri residue anchoring the peptide at the receptor transmembrane (TM) bundle level and the micelle, an E14-R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37^Cagri interaction with the receptor ECD. These features collectively enable non-specific binding and activation across different receptors. Both structural and functional analyses revealed Cagri's non-selective activation of G_s signaling pathways through CTR and AMY₁R. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938347","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":"Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance.","authors":"Xiao Ge, Guang-Ming Yang, Xiao-Long Zhang, Jing Cao, Ying-Jie Qing, San-Bing Shen, Yang Pan, Po Hu","doi":"10.1038/s41401-025-01636-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01636-1","url":null,"abstract":"<p><p>Mitochondrial DNA (mtDNA) damage and accumulation activate the cGAS-STING DNA-sensing pathway, which promotes immune clearance of tumor cells. Maintenance of the cytosolic level of mtDNA is key to sustain immune activation. T cell malignancies (T-CMs) are a general name of diseases with abnormal clonal proliferation of T lymphocytes at various stages. Immunotherapy of T-CMs is challenged by the lack of specific antigens to discriminate T-CMs from normal T cells. As intrinsic STING activation can promote the clearance of T-CMs by immune cells, we herein explored whether isoliensinine (IsoL), a natural compound from Nelumbinis Plumula could enhance NK clearance by mtDNA-mediated immune responses in tumor cells. To investigate whether IsoL modulated immune recognition and clearance of T-CMs, we pre-treated three T-CM cell lines (Jurkat, Molt4 and Hut102) with IsoL then co-cultured with NK-92MI cells. We showed that IsoL pre-treatment promoted cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1), an antioxidant enzyme. Loss of PRDX1 in T-CMs also induced ROS-dependent mitochondrial DNA damage, and blocked mitophagy by preventing accumulation of mature PINK1, which was required to initiate mitophagy via recruiting Parkin to the damaged mitochondria. Remarkably, IsoL could induce expression of activating ligands in vitro, enhance NK cell infiltrations, and increase apoptosis of T-CMs. Moreover, we demonstrated that IsoL could sensitize T-CMs for NK clearance in vitro and in vivo. These results suggest that IsoL could be a potential therapeutic agent to enhance immune therapy of T-CMs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938311","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}