Acta Pharmacologica Sinica最新文献_第5页

Long non-coding RNA STMN1P2 promotes breast cancer doxorubicin resistance by inhibiting pyroptosis through the hnRNPU-EZH2-TARF6-MALT1-caspase-1 pathway. 长链非编码RNA STMN1P2通过hnRNPU-EZH2-TARF6-MALT1-caspase-1途径抑制乳腺癌阿霉素耐药，促进乳腺癌阿霉素耐药。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-08 DOI: 10.1038/s41401-025-01653-0

You-Ping Jin, Bu-Jie Xu, Xiu-Fen Zhang, Xue Wang, Li Wang, Lu-Ying Li, Shu-Yi Chen, Ping Zhu, Xiu-Ling Zhi, Lei Lv, Chao-Fu Wang, Zheng-Lin Wang, Yang-Bai Sun, Ping Zhou

{"title":"Long non-coding RNA STMN1P2 promotes breast cancer doxorubicin resistance by inhibiting pyroptosis through the hnRNPU-EZH2-TARF6-MALT1-caspase-1 pathway.","authors":"You-Ping Jin, Bu-Jie Xu, Xiu-Fen Zhang, Xue Wang, Li Wang, Lu-Ying Li, Shu-Yi Chen, Ping Zhu, Xiu-Ling Zhi, Lei Lv, Chao-Fu Wang, Zheng-Lin Wang, Yang-Bai Sun, Ping Zhou","doi":"10.1038/s41401-025-01653-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01653-0","url":null,"abstract":"Chemotherapeutic resistance is a significant issue in the treatment of breast cancer, which is related to pyroptosis inhibition. Increasing evidence suggests that long non-coding RNAs (lncRNAs) contribute to tumorigenesis and drug resistance. In this study we investigated the role of the lncRNA STMN1P2 in doxorubicin resistance in breast cancer, as well as its correlation with pyroptosis inhibition. Our results showed that the expression levels of lncRNA STMN1P2 were significantly elevated in doxorubicin-resistant breast cancer tissues and cells. We demonstrated that knockdown of STMN1P2 reduced doxorubicin resistance in breast cancer cells; overexpression of STMN1P2 inhibited doxorubicin-induced pyroptosis by reducing the expression of NLRP3, ASC, caspase-1 and GSDMD. Furthermore, STMN1P2 directly bound to and positively regulated heterogeneous nuclear ribonucleoprotein U (hnRNPU), and knockdown of hnRNPU reversed the inhibitory effect of STMN1P2 on pyroptosis and its ability to promote chemoresistance. In doxorubicin-resistant cells, hnRNPU directly bound to enhancer of zeste homologue 2 (EZH2), and STMN1P2 enhanced hnRNPU recruitment of EZH2 and increased EZH2 protein stability. EZH2 acted as a transcription factor to inactivate TNF receptor-associated factor 6 (TRAF6), thereby repressing the binding of TRAF6 with MALT1 and caspase-1, attenuating the canonical pathways of pyroptosis. In MCF7/DOX cells xenograft nude mouse model, we demonstrated that knockdown of STMN1P2 significantly enhanced the suppression of doxorubicin on the tumour growth. This study provides new clues and approaches for the prevention and treatment of breast cancer chemoresistance.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028701","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

Salvianolic acid A from Salvia miltiorrhiza identified as a cap-dependent endonuclease inhibitor for pathogenic arenaviruses. 从丹参中提取的丹酚酸A被鉴定为致病性沙粒病毒的帽依赖内切酶抑制剂。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-03 DOI: 10.1038/s41401-025-01654-z

Xiao Gao, Yan Wu, Xiao-Xue He, Guo-Long Liu, Hai-Xia Yang, Jia Lu, Xue-Rui Zhu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Chan Yang, Shu Shen, Fei Deng, Wei Xu, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan

{"title":"Salvianolic acid A from Salvia miltiorrhiza identified as a cap-dependent endonuclease inhibitor for pathogenic arenaviruses.","authors":"Xiao Gao, Yan Wu, Xiao-Xue He, Guo-Long Liu, Hai-Xia Yang, Jia Lu, Xue-Rui Zhu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Chan Yang, Shu Shen, Fei Deng, Wei Xu, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan","doi":"10.1038/s41401-025-01654-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01654-z","url":null,"abstract":"Negative-stranded segmented RNA viruses (NSVs) employ a cap-snatching mechanism for transcription, which makes cap-dependent endonuclease (CEN) an attractive target for drug development. Pathogenic arenaviruses pose a serious threat to humans, yet no approved treatments exist, underscoring the importance of discovering novel compounds targeting arenaviral CENs. Therefore, this study aimed to identify novel CEN inhibitors for arenaviruses and investigate their antiviral mechanisms. A high-throughput screening system based on enzymatic activity of CEN was established for discovering inhibitors of lymphocytic choriomeningitis virus (LCMV). Several hit compounds were screened from a vast natural product library, and then evaluated for both toxicity and inhibition through cellular and animal experiments. One candidate compound was finally identified, and its mechanism of action on CEN was elucidated through simulation analysis and biochemical studies. Moreover, its broad-spectrum effects were investigated among pathogenic arenaviruses as well as representative NSVs. Consequently, salvianolic acid A (SAA) from Salvia miltiorrhiza was identified as a promising compound that effectively inhibited LCMV infection and significantly reduced the viral load via intravenous administration. It was shown to bind to the active pocket of arenaviral CENs while chelating their metal ions through its acid carboxyl group, acting in a substrate-competitive manner. Additionally, SAA exhibited broad-spectrum inhibition of pathogenic arenaviruses as well as representative viruses from the order Bunyavirales. This study identified SAA as a novel CEN inhibitor, particularly for pathogenic arenaviruses, showcasing its promise for antiviral drug development.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991260","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

BMP1 inhibitor UK383367 improves MI-induced cardiac remodeling and fibrosis in mice via ameliorating macrophage polarization and mitochondrial dysfunction. BMP1抑制剂UK383367通过改善巨噬细胞极化和线粒体功能障碍改善mi诱导的小鼠心脏重塑和纤维化。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-02 DOI: 10.1038/s41401-025-01655-y

Cheng-Hu Guo, Qian-Qian Wang, Jia-Qi Li, Wei Ji, Lin Chen, Mei-Ling Chang, Lian-Yue Ma, Xiao-Ling Liu, Mei Ni

{"title":"BMP1 inhibitor UK383367 improves MI-induced cardiac remodeling and fibrosis in mice via ameliorating macrophage polarization and mitochondrial dysfunction.","authors":"Cheng-Hu Guo, Qian-Qian Wang, Jia-Qi Li, Wei Ji, Lin Chen, Mei-Ling Chang, Lian-Yue Ma, Xiao-Ling Liu, Mei Ni","doi":"10.1038/s41401-025-01655-y","DOIUrl":"10.1038/s41401-025-01655-y","url":null,"abstract":"Despite optimized guideline-directed medical therapy, patients with myocardial infarction (MI) often develop heart failure (HF) primarily because of excessive fibrosis. Bone morphogenetic protein 1 (BMP1) plays a critical role in the fibrotic process, yet its specific role in post-MI myocardial fibrosis remains unclear. In this study, we investigated the complex dynamics between BMP1 and fibrotic processes, offering critical insights for novel strategies to mitigate pathological fibrosis in cardiovascular diseases. An experimental MI model was established in mice by ligating the left anterior descending (LAD) coronary artery. We found that the expression levels of BMP1 were significantly elevated in both the serum of MI patients and the cardiac tissues of MI mice. Administration of the BMP1 inhibitor UK383367 (2 mg/kg, i.p., t.i.d., starting the day of myocardial infarction modeling and maintained for 7 days) in MI mice markedly improved cardiac function, reduced myocardial fibrosis, and attenuated the expression of proinflammatory cytokines, including TNF-α, IL-6 and MCP-1. Proteomic profiling revealed that BMP1 was associated with inflammation and oxidative phosphorylation pathways after MI. We demonstrated that UK383367 (250, 500, and 1000 nM) dose-dependently attenuated M1 macrophage polarization, protected mitochondrial function in lipopolysaccharide-stimulated primary macrophages, and inhibited collagen synthesis in Ang II-stimulated cardiac fibroblasts. Overall, these results reveal a pivotal yet detrimental role for BMP1 in driving myocardial fibrosis and amplifying inflammatory cascades after MI. This study highlights the therapeutic potential of the BMP1 inhibitor UK383367 as a promising alternative to conventional antifibrotic strategies, potentially curbing the progression toward HF.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938369","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

Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells. Sirtuin 6通过维持血管平滑肌细胞的线粒体稳态减轻胸主动脉瘤的进展。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-02 DOI: 10.1038/s41401-025-01628-1

Xiao-Ting Yu, Nan Zhao, Yu-Tao Ma, Jin-Meng Jia, Yan-Ting Song, Xiao-Yan Liu, Yao Xiao, Bo Jia, Guang-Ming Li, Jin-Han He, Sheng Wang, Jun-Ming Zhu, Frank J Gonzalez, Ai-Juan Qu

{"title":"Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells.","authors":"Xiao-Ting Yu, Nan Zhao, Yu-Tao Ma, Jin-Meng Jia, Yan-Ting Song, Xiao-Yan Liu, Yao Xiao, Bo Jia, Guang-Ming Li, Jin-Han He, Sheng Wang, Jun-Ming Zhu, Frank J Gonzalez, Ai-Juan Qu","doi":"10.1038/s41401-025-01628-1","DOIUrl":"10.1038/s41401-025-01628-1","url":null,"abstract":"Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938307","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

Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor. P2X1受体多配体结合机制的结构基础。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-02 DOI: 10.1038/s41401-025-01512-y

Yu-Ting Qiang, Peng-Peng Wu, Xin Liu, Li Peng, Li-Ke Zhao, Ya-Ting Chen, Zhao-Bing Gao, Qiang Zhao, Kun Chen

{"title":"Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor.","authors":"Yu-Ting Qiang, Peng-Peng Wu, Xin Liu, Li Peng, Li-Ke Zhao, Ya-Ting Chen, Zhao-Bing Gao, Qiang Zhao, Kun Chen","doi":"10.1038/s41401-025-01512-y","DOIUrl":"10.1038/s41401-025-01512-y","url":null,"abstract":"As important modulators of human purinergic signaling, P2X1 receptors form homotrimers to transport calcium, regulating multiple physiological processes, and are long regarded as promising therapeutic targets for male contraception and inflammation. However, the development of drugs that target the P2X1 receptor, such as the antagonist NF449, is greatly hindered by the unclear molecular mechanism of ligand binding modes and receptor activation. Here, we report the structures of the P2X1 receptor in complex with the endogenous agonist ATP or the competitive antagonist NF449. The P2X1 receptor displays distinct conformational features when bound to different types of compounds. Despite coupling to the agonist ATP, the receptor adopts a desensitized conformation that arrests the ions in the transmembrane (TM) domain, aligning with the nature of the high desensitization rates of the P2X1 receptor within the P2X family. Interestingly, the antagonist NF449 not only occupies the orthosteric pocket of ATP but also interacts with the dorsal fin, left flipper, and head domains, suggesting a unique binding mode to perform both orthosteric and allosteric mechanisms of NF449 inhibition. Intriguingly, a novel lipid binding site adjacent to the TM helices and lower body of P2X1, which is critical for receptor activation, is identified. Further functional assay results and structural alignments reveal the high conservation of this lipid binding site in P2X receptors, indicating important modulatory roles upon lipid binding. Taken together, these findings greatly increase our understanding of the ligand binding modes and multiple modulatory mechanisms of the P2X1 receptor and shed light on the further development of P2X1-selective antagonists.Keywords: Structural biology; Ligand binding mode; Ion channel; Purinergic P2X1 receptor.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2564-2573"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771019","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

Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma. 脂素1依赖的SREBPs转录失活有助于多发性骨髓瘤中selinexor的敏感性。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-14 DOI: 10.1038/s41401-025-01553-3

Jun-Ying Wang, Meng-Ping Chen, Jin-Xing Jiang, Yi-Ke Wan, Xin Li, Yi-Wei Zhang, Yi Fang, Hong-Hui Huang, Zhao-Yu Qin, Jian Hou

{"title":"Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma.","authors":"Jun-Ying Wang, Meng-Ping Chen, Jin-Xing Jiang, Yi-Ke Wan, Xin Li, Yi-Wei Zhang, Yi Fang, Hong-Hui Huang, Zhao-Yu Qin, Jian Hou","doi":"10.1038/s41401-025-01553-3","DOIUrl":"10.1038/s41401-025-01553-3","url":null,"abstract":"Selective nuclear export inhibitor selinexor (SEL) represents a promising therapeutic strategy for relapsed/refractory multiple myeloma (RRMM). But its mechanisms of action as well as factors that influence therapeutic responses have not been fully characterized yet. In this study we employed catTFRE proteomics technique to profile changes in nuclear abundance of activated transcription factors (TFs)/co-factors (TCs) in myeloma cells following SEL treatment. We found that pharmacological inhibition of exportin-1 (XPO1) by SEL leads to a significant nuclear accumulation of Lipin1 in NCI-H929 cells. Nuclear-localized Lipin1 acted as a transcriptional cofactor that suppressed the transcriptional activity of SREBPs. By performing subcellular localization analysis, molecular docking, co-immunoprecipitation and other assays, we demonstrated that Lipin1 was subjected to XPO1-dependent nuclear export. We demonstrated that SEL downregulated the expression of key lipogenesis-related genes regulated by SREBPs including FASN, SCD, DHCR24 and FDPS, leading to reduced fatty acid and cholesterol synthesis in MM cell lines and primary CD138+ cells. Using shRNA-mediated knockdown assays, we elucidated the critical role of Lipin1 in mediating the inhibitory effects of SEL on the SREBPs pathway and its contribution to SEL sensitivity both in vitro and in murine xenograft models. In conclusion, we reveal a novel mechanism by which SEL downregulates cellular lipid biosynthesis, thereby inhibiting the proliferation of myeloma cells. This study highlights the critical role of Lipin1 in the anti-myeloma effects of SEL, suggesting its potential as a biomarker for identifying patients who are most likely to benefit from SEL-based therapies.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2496-2508"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955358","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

Identification of Licoflavone C as a cap-dependent endonuclease inhibitor against severe fever with thrombocytopenia syndrome virus. 甘草黄酮C作为帽依赖性核酸内切酶抑制剂抗发热伴血小板减少综合征病毒的鉴定。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-01 DOI: 10.1038/s41401-025-01533-7

Xiao Gao, Xiao-Xue He, Xue-Rui Zhu, Yan Wu, Jia Lu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan

{"title":"Identification of Licoflavone C as a cap-dependent endonuclease inhibitor against severe fever with thrombocytopenia syndrome virus.","authors":"Xiao Gao, Xiao-Xue He, Xue-Rui Zhu, Yan Wu, Jia Lu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan","doi":"10.1038/s41401-025-01533-7","DOIUrl":"10.1038/s41401-025-01533-7","url":null,"abstract":"Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with a high fatality rate. Currently no approved drugs or vaccines are available against it. Sharing a common replication mechanism with negative-stranded, segmented viruses (NSVs), SFTSV utilizes a cap-dependent endonuclease (CEN) domain of the L segment to execute the cap-snatching process upon genome transcription initiation. Given the crucial role of CEN in the life cycle of NSVs, it is considered a promising target for discovery of antiviral agents against SFTSV. In this study, we established a high-throughput FRET-based enzymatic screening system to discover inhibitors of SFTSV CEN from a chemical library containing 3467 natural compounds. Finally, three compounds, i.e., Licoflavone C, 3,4-dicaffeoylquinic acid, and oleanolic acid displayed exceptional antiviral effects and minimal cytotoxicity. Licoflavone C (EC50 = 1.85 μM) was selected for further investigation. Administration of Licoflavone C (20 mg/kg, i.v.) significantly reduced tissue viral loads in SFTSV-challenged mouse model. We demonstrated that Licoflavone C did not directly bind to the active pocket of SFTSV CEN but disrupted its active conformation, resulting in substrate non-competitive inhibition. Licoflavone C also exhibited broad-spectrum inhibition on several NSV CENs (HRTV, GTV, and LCMV) besides SFTSV. Furthermore, 15 analogs of Licoflavone C sharing a typical flavonoid structure were verified for targeting SFTSV CEN and exhibiting antiviral activities. In conclusion, Licoflavone C is a promising inhibitor of SFTSV, offering insights into targeting CEN with flavonoids in drug discovery.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2482-2495"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762635","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

JOSD2 alleviates acute kidney injury through deubiquitinating SIRT7 and negativity regulating SIRT7-NF-κB inflammatory pathway in renal tubular epithelial cells. JOSD2通过去泛素化SIRT7和负性调节肾小管上皮细胞SIRT7- nf -κB炎症通路减轻急性肾损伤。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-11 DOI: 10.1038/s41401-025-01546-2

Ying Zhao, Qing-Qing Zhao, Shi-Jie Fan, Di-Yun Xu, Li-Ming Lin, Wu Luo, Bo-Zhi Ye, Chun-Peng Zou, Hong Zhu, Zai-Shou Zhuang, Yun-Jie Zhao, Guang Liang

{"title":"JOSD2 alleviates acute kidney injury through deubiquitinating SIRT7 and negativity regulating SIRT7-NF-κB inflammatory pathway in renal tubular epithelial cells.","authors":"Ying Zhao, Qing-Qing Zhao, Shi-Jie Fan, Di-Yun Xu, Li-Ming Lin, Wu Luo, Bo-Zhi Ye, Chun-Peng Zou, Hong Zhu, Zai-Shou Zhuang, Yun-Jie Zhao, Guang Liang","doi":"10.1038/s41401-025-01546-2","DOIUrl":"10.1038/s41401-025-01546-2","url":null,"abstract":"Acute kidney injury (AKI), triggered by various stimuli including ischemia-reperfusion, nephrotoxic insult, and sepsis, is characterized by an abrupt deterioration in kidney function. Ubiquitination is a post-translational modification of proteins that plays a critical role in the pathogenesis and progression of AKI. In this study, we aimed to investigate the role and underlying mechanism of the deubiquitinating enzyme Josephin Domain-containing protein 2 (JOSD2) in AKI. We found that deficiency of JOSD2 exacerbated renal tubular injury and inflammation in AKI mice induced by cisplatin or ischemia-reperfusion injury. Conversely, the specific overexpression of JOSD2 in renal tubular epithelial cells effectively prevented renal tubular injury and inflammation induced in AKI mice. Mechanistically, we identified Sirtuin 7 (SIRT7) as a potential substrate of JOSD2 through mass spectrometry combined with co-immunoprecipitation analysis. JOSD2 removes the K63-linked ubiquitination of SIRT7 via its active site C24 and promotes P62-mediated autophagic degradation of SIRT7, which subsequently prevents the phosphorylation and nuclear translocation of P65 and reduces inflammatory responses in renal tubular epithelial cells. Our study reveals the role of the JOSD2-SIRT7 axis in regulating AKI-induced renal inflammation and highlights the potential of JOSD2 as a promising therapeutic target for AKI.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2468-2481"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965935","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 neurodegenerative disease-associated protein aggregation with proximity-inducing modalities. 以邻近诱导方式靶向神经退行性疾病相关蛋白聚集。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-07 DOI: 10.1038/s41401-025-01538-2

Rui-Xin Ge, Miao Chen, Qing-Chao Li, Min Liu, Jun Zhou, Song-Bo Xie

{"title":"Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities.","authors":"Rui-Xin Ge, Miao Chen, Qing-Chao Li, Min Liu, Jun Zhou, Song-Bo Xie","doi":"10.1038/s41401-025-01538-2","DOIUrl":"10.1038/s41401-025-01538-2","url":null,"abstract":"Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunction and anatomical changes caused by neuron loss and gliosis, ultimately leading to severe declines in brain function. While these disorders arise from a variety of pathological mechanisms, a common molecular feature is the accumulation of misfolded proteins, which occurs both inside and outside neurons. For example, Alzheimer's disease (AD) is defined by extracellular β-amyloid plaques and intracellular tau neurofibrillary tangles. These pathological protein aggregates are often resistant to traditional small molecule drugs. Recent advances in proximity-inducing chimeras such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTACs), autophagy-targeted chimeras (AUTOTACs), dephosphorylation-targeting chimeras (DEPTACs) and ribonuclease-targeting chimeras (RIBOTACs) offer promising strategies to eliminate pathological proteins or mRNAs through intracellular degradation pathways. These innovative approaches open avenues for developing new therapies for NDDs. In this review we summarize the regulatory mechanisms of protein aggregation, highlight the advancements in proximity-inducing modalities for NDDs, and discuss the current challenges and future directions in therapeutic development.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2337-2346"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802223","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

Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice. 孕烷X受体通过激活yes相关蛋白减轻脓毒症诱导的小鼠肝损伤。

IF 8.4 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-09-01 Epub Date: 2025-04-15 DOI: 10.1038/s41401-025-01552-4

Cheng-Hua Wu, Shuang Hu, Dan Li, Xiao-Wen Jiang, Hui Ou-Yang, Guo-Fang Bi, Peng Wang, Feng-Ting Liang, Wen-Hong Zhou, Xiao Yang, Jian-Hong Fang, Hui-Chang Bi

{"title":"Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice.","authors":"Cheng-Hua Wu, Shuang Hu, Dan Li, Xiao-Wen Jiang, Hui Ou-Yang, Guo-Fang Bi, Peng Wang, Feng-Ting Liang, Wen-Hong Zhou, Xiao Yang, Jian-Hong Fang, Hui-Chang Bi","doi":"10.1038/s41401-025-01552-4","DOIUrl":"10.1038/s41401-025-01552-4","url":null,"abstract":"The severity of sepsis is attributed to excessive inflammatory responses leading to liver injury. Pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, has been implicated in regulating inflammation and liver regeneration. This study aimed to investigate the role of PXR in sepsis-induced liver injury and the underlying mechanisms. Sepsis models were established in mice, the mice were administered the typical mouse PXR agonist PCN (100 mg·kg-1·d-1, i.p.) for 3 consecutive days in advance, then subjected to CLP operation or LPS administration 1 h after the last administration of PCN. The results showed that PCN pretreatment significantly increased the survival rate of septic mice, while the survival rate was reduced after the knockout of Pxr. In addition, PCN pretreatment effectively alleviated sepsis-induced liver injury. In Pxr knockout mice, liver injury was more severe, whereas the protective effects of PCN pretreatment were abolished. Mechanistically, PCN pretreatment significantly upregulated the expression of yes-associated protein (YAP) and its downstream targets and decreased the level of phosphorylated nuclear factor-κB (NF-κB). Moreover, liver-specific knockdown of Yap blocked the protective effects of PCN pretreatment against sepsis-induced liver injury and downregulated the phosphorylation level of NF-κB. In summary, this study demonstrated that PXR activation protects against sepsis-induced liver injury through activation of the YAP signaling pathway, providing a new strategy for the diagnosis and treatment of sepsis-induced liver injury.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2423-2435"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959351","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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