Acta Pharmacologica Sinica最新文献

{"title":"Editorial Expression of Concern: n-Butylidenephthalide induced apoptosis in the A549 human lung adenocarcinoma cell line by coupled down-regulation of AP-2α and telomerase activity.","authors":"Chyou-Wei Wei, Chai-Ching Lin, Yung-Luen Yu, Chai-Yi Lin, Po-Cheng Lin, Min-Tze Wu, Cheng-Jueng Chen, Wen-Liang Chang, Shinn-Zong Lin, Yi-Lin Sophia Chen, Horng-Jyh Harn","doi":"10.1038/s41401-025-01660-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01660-1","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123806","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":"TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice.","authors":"Yi-Pan Zhu, Jing Sun, Xin-Yu Cao, Xin-Yu Ding, Yu-Ying Wang, Qiu-Ju Han, Jing-Ying Wang, Lu-Yuan Li, Zhi-Song Zhang","doi":"10.1038/s41401-025-01663-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01663-y","url":null,"abstract":"<p><p>Myeloid-derived suppressor cells (MDSCs) are a category of immature myeloid cells that have an important function in suppressing immune responses in a variety of pathological settings. Thus, MDSCs are the subject of intensive studies regarding their recruitment, expulsion, deactivation, and maturation promotion. Tumor necrosis factor superfamily member 15 (TNFSF15) is produced largely by vascular endothelial cells in mature blood vessels with expression also observed in tumor-associated macrophages (TAMs) and dendritic cells (DCs) within the tumor stroma. In addition to inhibiting the proliferation of vascular endothelial cells and the differentiation of bone marrow-derived endothelial cell progenitors, TNFSF15 is able to promote the maturation of DC, as well as to modulate the polarization of naive M2-macrophages into M1-macrophages capable of eliminating cancer cells, and activate T-cell. In this study, we investigated whether a recombinant TNFSF15 results in a substantial reduction of MDSC accumulation in Lewis lung cancer (LLC) tumor-bearing mice. LLC allograft model mice were administered recombinant TNFSF15 (5 mg·kg^-1·d^-1, i.p.) for 7 consecutive days. The tumor, bone marrow and spleen were retrieved on Day 8 and analyzed using flow cytometry or immunofluorescence staining. We showed that TNFSF15 treatment significantly inhibited the tumor growth, and caused a substantial reduction of MDSC accumulation in the tumors. The proportions of MDSC in the bone marrows and the spleens were also reduced. The diminished MDSC was mainly the monocyte-like MDSC (M-MDSC) subtype. Additionally, the reduction in M-MDSC population was accompanied by an increase of the proportions of macrophages and DCs in the tumors. We demonstrated that TNFSF15 promoted M-MDSC differentiation by activating the JAK1/STAT3 signaling pathway. Moreover, the treatment gave rise to a markedly escalated accumulation of cytotoxic T cells in the tumors, attributing to tumor growth inhibition. Our results support the view that TNFSF15-driven differentiation of M-MDSC into DCs and macrophages, and the subsequent activation of T cells, may contribute partially to reinstitution of immunity in the tumor microenvironment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090987","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":"Correction: magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling.","authors":"Yan-Zi Yang, Xiao-Juan Zhao, Hong-Jiang Xu, Shan-Chun Wang, Ying Pan, Shui-Juan Wang, Qiang Xu, Rui-Qing Jiao, Hong-Mei Gu, Ling-Dong Kong","doi":"10.1038/s41401-025-01656-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01656-x","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084848","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":"Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans.","authors":"Zi-Tao Guo, Hong Wang, Ning-Jie Xie, Yu-Fan Zhou, Meng-Lin Zhang, Xin-Yao Kang, Jue Wang, Qing Zhu, Xiao-Yan Chen","doi":"10.1038/s41401-025-01658-9","DOIUrl":"https://doi.org/10.1038/s41401-025-01658-9","url":null,"abstract":"<p><p>Morphine-6-glucuronide (M6G), the active metabolite of morphine, is currently in clinical development due to its higher analgesic activity. In humans, intravenously administered M6G was predominantly eliminated unchanged through the kidney, whereas it was excreted into the urine as parent drug as well as its metabolites morphine and M3G in normal rats. In bile-duct-cannulated rats, however, bile excretion of the parent drug was the main route of clearance. In the study, we investigated the mechanisms underlying the species differences in vivo disposition of M6G. In hepatocyte uptake assay, we showed that M6G uptake in rat hepatocytes was 75-fold higher than that in human hepatocytes. Hepatic uptake transporter phenotyping study identified M6G as a substrate for rat rOatplal, rOatpla4, rOatp1b2, as well as for human hOATP1B1 and hOATP1B3. Among these, rOatps exhibited significantly stronger uptake of M6G compared to hOATPs. Furthermore, M6G was not a substrate for the canalicular efflux transporters MDR1, hBCRP/rBcrp, hBSEP/rBsep, and hMRP2, but it was recognized by rMrp2. These findings aligned with the observation that M6G exhibited significant biliary excretion in the rat sandwich cultured hepatocyte (SCH) model, but not in the human SCH. Additionally, no species differences were observed in renal uptake mediated by OAT3. Overall, M6G underwent renal clearance in humans via glomerular filtration and active secretion primarily mediated by hOAT3. Although a portion of M6G was also eliminated through the kidney in rats, the majority was subjected to enterohepatic circulation mediated primarily by rOatps and rMrp2, leading to the formation of morphine and M3G, which were subsequently excreted in the urine. The marked difference in the uptake activities of sinusoidal transporters hOATPs/rOatps and the substrate specificity of canalicular transporters hMRP2/rMrp2 were critical factors underlying the species differences in the hepatobiliary disposition of M6G.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068833","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":"Tigecycline suppresses colon cancer stem cells and impairs tumor engraftment by targeting SNAI1-regulated epithelial-mesenchymal transition.","authors":"Antonio Jesús Ruiz-Malagón, María Jesús Rodríguez-Sojo, Jorge García-García, Ailec Ho-Plagaro, Federico García, Teresa Vezza, Eduardo Redondo-Cerezo, Carmen Griñán-Lisón, Juan Antonio Marchal, María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales, Julio Gálvez","doi":"10.1038/s41401-025-01629-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01629-0","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) play a key role in the progression of colorectal cancer (CRC). The high heterogeneity of CSCs has hindered the clinical application of CSC-targeting therapies. Tetracyclines are drugs with therapeutic potentials beyond their antibiotic activity. We previously demonstrated the efficacy of tigecycline, a third-generation tetracycline, against a model of colitis-associated colorectal cancer, primarily focusing on its immunomodulatory role with a preliminary assessment of its impact on stemness. In this study we characterize the effects of tigecycline on colon CSCs in vitro and in a CRC xenograft model, with special attention on the signaling pathways involved and the modulation of the gut microbiota. We generated secondary colonospheres from two colon tumor cell lines HCT116 and CMT93, and evaluated the effect of tigecycline on CSCs properties. We showed that tigecycline (25, 50 μM) effectively reduced colon CD133⁺CD44⁺LGR5⁺ALDH⁺ subpopulations and their viability, self-renewal and migratory capacity. Moreover, tigecycline treatment hindered epithelial-mesenchymal transition (EMT) process through targeting SNAI1 and β-catenin, resulting in an upregulation of epithelial markers (E-cadherin) and a downregulation of pluripotency and mesenchymal ones (Vimentin, N-cadherin, SOX2, NANOG, MIR155, MIR146). This effect was confirmed in two independent CRC-xenograft murine models in which tigecycline administration led to a reduction in tumor volume. Finally, CRC samples were taken from HCT116 xenograft model mice for analysis of CSCs-related signaling pathways and stools were collected for gut microbiome metagenomic analysis. We found that the antibiotic modulated gut dysbiosis by increasing the abundance of beneficial bacterial species such as Parabacteroides sp., which were involved in metabolic pathways that hindered SNAI1-Wnt-β-catenin signaling. These results reinforce the new role of tigecycline in the therapy of CRC and demonstrate for the first time the effect of tigecycline on colon CSCs and their malignancies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051624","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":"Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.","authors":"Lan-Lan Li, Chao-Jun Sun, Xiao-Tong Mo, Yun Xing, Tong Zhang, Heng Zhang, Nan Zhao, Xiao-Feng Zeng, Sha-Sha Wang, Yan-Yan Meng, Sai-Yang Xie, Wei Deng","doi":"10.1038/s41401-025-01637-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01637-0","url":null,"abstract":"<p><p>Pathological cardiac hypertrophy as a major contributor to heart failure is characterized by complicated mechanisms. Fumarate hydratase (FH) is a crucial enzyme in the tricarboxylic acid cycle. FH mutations and dysfunction have been implicated in various pathological processes including hereditary leiomyomatosis and renal cell cancer, neurodegenerative diseases, metabolic syndrome and cardiovascular diseases. In this study we investigated the role of FH in cardiac hypertrophy. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery as well as in neonatal rat cardiomyocytes (NRCMs) by phenylephrine (PE) stimulation. We showed that the expression levels of FH were gradually increased with development of cardiac hypertrophy in TAC mice. Cardiomyocyte-specific overexpression of FH by intravenous injection of recombinant adeno-associated virus serotype 9 (AAV9) carrying FH two weeks before TAC surgery prevented the morphological changes, cardiac dysfunction and remodeling in TAC mice; FH overexpression also significantly attenuated PE-induced hypertrophy in NRCMs along with suppressed expression of hypertrophic markers ANP, BNP and β-MHC. We demonstrated that FH overexpression alleviated TAC-induced mitochondrial structural damage in cardiomyocytes and facilitated metabolic remodeling. RNA sequencing and untargeted metabolomics revealed that FH overexpression mitigated myocardial remodeling and mitochondrial metabolism dysfunction in TAC mice mainly by suppressing the transcription factor SREBP and reducing the gene expression of elongation of very long chain fatty acids protein 7 (Elovl7). Overexpression of Elovl7 reversed the protective effects of FH in both TAC mice and PE-stimulated NRCMs. Knockdown of the transcription factor SREBP reduced Elovl7 expression, thereby exerting cardioprotective effects. In conclusion, we demonstrate that FH overexpression prevents cardiac hypertrophy in mice by regulating glucose and lipid metabolism through the malate-SREBP-Elovl7 pathway.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051631","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":"Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis.","authors":"Hao Chen, Lin Yang, Xiao-Feng Li, Si-Yuan Han, Qi Zhao, Rong-Cheng Xiao, Zi-Yao Ou, Ling Fang, Yan Du","doi":"10.1038/s41401-025-01651-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01651-2","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) remains a predominant cause of chronic hepatic pathology, and effective therapeutic strategies are needed. Krüppel-like factor 15 (KLF15) is a member of the KLF family of zinc-finger transcription factors and is ubiquitously expressed in metabolically active tissues, with a particularly high abundance in the liver. KLF15 has been implicated in various hepatic disorders. In this study, we investigated the pathophysiological role of KLF15 in ALD. We established a National Institute on Alcohol Abuse and Alcoholism (NIAAA) model in mice by feeding them an ethanol Lieber-DeCarli liquid diet containing 5% (vol/vol) ethanol for 10 days. EtOH-fed mice were administered binge ethanol gavage (5 g/kg, body weight) on D11. We observed that the expression levels of KLF15 were significantly decreased in the livers of ALD patients and model mice. Overexpression of KLF15 conferred substantial protective effects in EtOH-fed mice, as evidenced by attenuated hepatic injury, apoptosis, steatosis and inflammation. In ethanol-treated AML-12 cells, overexpression of KLF15 reduced apoptosis and steatosis, whereas KLF15 knockdown exacerbated these pathological features. By performing RNA-seq and bioinformatics analyses, we observed that KLF15 regulated the AKT pathway by directly binding to the PFKFB3 promoter (-128 to -121). The physical interaction between PFKFB3 and AKT1 was further verified by Co-IP and molecular docking. These results suggest that KLF15 is a pivotal regulator of ALD pathogenesis through modulation of the PFKFB3/AKT axis, highlighting its potential as a novel therapeutic target for ALD intervention.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038728","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":"GluN2A-NMDA receptor inhibition disinhibits the prefrontal cortex, reduces forced swim immobility, and impairs sensorimotor gating.","authors":"Yuan-Ping Dong, Yun Wu, Yi-Lu Zhao, Yu-Min Chen, Tong-Ye Liu, Yi-He Zhang, Jie-Ying Xie, Jin-Feng Zhang, Han Zhang, He Chen, Yu Peng, Chun-Lei Zhang, Andrew R Rau, Kasper B Hansen, Hai-Bing Xu, Feng Yi","doi":"10.1038/s41401-025-01643-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01643-2","url":null,"abstract":"<p><p>Recent investigations into the rapid antidepressant effects of ketamine, along with studies on schizophrenia-related susceptibility genes, have highlighted the GluN2A subunit as a critical regulator of both emotion and cognition. However, the specific impacts of acute pharmacological inhibition of GluN2A-containing NMDA receptors on brain microcircuits and the subsequent behavioral consequences remain poorly understood. In this study, we first examined the effects of MPX-004, a selective GluN2A NMDA receptor inhibitor, on behavior within the dorsomedial prefrontal cortex (dmPFC). Local administration of MPX-004 in the dmPFC led to a reduced immobility duration in the forced swim test, an acute antidepressant-like effect, impairments in sensorimotor gating, and a schizophrenia-like phenotype. In vivo multiple-channel recordings and c-Fos staining revealed that MPX-004 decreases the activity of parvalbumin-expressing interneurons (PV-INs) and increases the activity of pyramidal neurons (PYNs). In vivo patch-clamp recordings further confirmed that PV-IN inactivation leads to an elevated PYN firing rate in the PFC. In vitro whole-cell recordings demonstrated that PV-INs receive stronger excitatory synaptic input and respond more robustly to presynaptic stimulation than do somatostatin-expressing interneurons (SST-INs) and PYNs, rendering them susceptible to GluN2A inhibition. Finally, the specific knockdown of GluN2A in prefrontal PV-INs abolished the behavioral effects of MPX-004, underscoring a critical role of the GluN2A-mediated modulation of PV-INs in these phenotypes. Together, these findings reveal that PV-INs are particularly vulnerable to GluN2A inhibition, leading to disinhibition of prefrontal circuits and resulting in both antidepressant-like and schizophrenia-like behaviors.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032333","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":"HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade.","authors":"Wen-Jing Li, Kai-Ge Kang, Yu-Xiang Zhang, Xin-Xin Zhao, Xi Zhu, Jiao Tang, Yong-Peng Li, Hao-Yu Fu, Qing Yao, Lei Wang, Li-Guang Lou","doi":"10.1038/s41401-025-01647-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01647-y","url":null,"abstract":"<p><p>The anti-HER2 antibody‒drug conjugate (ADC) DS-8201 presents new hope for patients with advanced HER2-positive tumors. Its clinical application, however, is hindered by serious adverse reactions and reduced efficacy following long-term treatment. In this study, we investigated the factors influencing the sensitivity of DS-8201 and developed effective combination regimens to optimize its therapeutic efficacy. We showed that HER3 upregulation diminished the sensitivity of HER2-positive tumor cells to DS-8201. We found that DS-8201 treatment activated DNA damage repair responses in BT-474 cells, in which the ATR kinase pathway induced the expression of the HER3 transcription factor FoxO1, leading to increased HER3 levels. This process was triggered by the payload component of DS-8201, the topoisomerase I inhibitor DXd, rather than the antibody. Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032403","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":"Antiemetic drug fosaprepitant exerts anti-tumor effects against NSCLC by targeting FAK to inhibit AKT and JNK/c-Jun pathways.","authors":"Ying Wang, Yu-Na Shao, Chen-Kang Ma, Chen-Ying Shu, Yi-Hua Zhang, Di Lu, Hui-Ling Zhang, Jian-Jie Zhu, Yuan-Yuan Zeng, Jian-Jun Li, Zhao-Wei Yan, Ze-Yi Liu","doi":"10.1038/s41401-025-01645-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01645-0","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is an aggressive malignancy with a poor prognosis. Abnormal expression of focal adhesion kinase (FAK) is closely linked to NSCLC progression, highlighting the need for effective FAK inhibitors in NSCLC treatment. In this study we conducted high-throughput virtual screening combined with cellular assays to identify potential FAK inhibitors for NSCLC treatment. Fosaprepitant (FOS), a clinical antiemetic drug, exhibited a high affinity for FAK with a K_D value of 4.35 × 10⁻⁵ M. The direct interaction between FOS and FAK was confirmed by molecular docking, molecular dynamics, drug affinity responsive target stability and surface plasmon resonance analysis. We showed that FOS (15, 25 μM) dose-dependently inhibited the proliferation, migration and invasion of A549 and H1299 cells by targeting FAK. The IC₅₀ values in inhibiting the cell viability at 24 h were 73.05 and 126.1 μM, respectively. Knockdown FAK reversed the inhibitory effects of FOS on A549 cells. Using RNA sequencing and Western blotting analysis, we demonstrated that FOS treatment led to downregulation of the AKT and JNK/c-Jun signaling pathways in A549 and H1299 cells. Importantly, point mutation analyses revealed that FOS primarily targeted the Y925 phosphorylation site on FAK. In A549 cells xenograft nude mouse model, administration of FOS (20, 60 mg/kg, i.p. every 2 d for 2 weeks) dose-dependently suppressed the tumor growth. Collectively, FOS exhibits significant anti-NSCLC activity both in vitro and in vivo by binding to FAK and inhibiting its phosphorylation, thereby blocking the AKT and JNK/c-Jun signaling pathways. These results suggest FOS as a novel FAK inhibitor for NSCLC treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032368","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}