Acta Pharmaceutica Sinica. B最新文献

{"title":"Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors","authors":"Xiong Zhang ,&nbsp;Yatian Yang ,&nbsp;Hongye Zou ,&nbsp;Yang Yang ,&nbsp;Xingling Zheng ,&nbsp;Eva Corey ,&nbsp;Amina Zoubeidi ,&nbsp;Nicolas Mitsiades ,&nbsp;Ai-Ming Yu ,&nbsp;Yuanpei Li ,&nbsp;Hong-Wu Chen","doi":"10.1016/j.apsb.2025.01.007","DOIUrl":"10.1016/j.apsb.2025.01.007","url":null,"abstract":"<div><div>Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as <em>POU3F2</em> (BRN2), <em>ASCL1/2</em>, <em>NeuroD1</em>, <em>SOX2/9</em>, <em>RUNX1/2</em> and <em>DLL3</em>. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both <em>de novo</em> neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1415-1429"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776842","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":"Dihydromyricetin mitigates abdominal aortic aneurysm via transcriptional and post-transcriptional regulation of heme oxygenase-1 in vascular smooth muscle cells","authors":"Weile Ye ,&nbsp;Pinglian Yang ,&nbsp;Mei Jin ,&nbsp;Jiami Zou ,&nbsp;Zhihua Zheng ,&nbsp;Yuanyuan Li ,&nbsp;Dongmei Zhang ,&nbsp;Wencai Ye ,&nbsp;Zunnan Huang ,&nbsp;Jiaojiao Wang ,&nbsp;Zhiping Liu","doi":"10.1016/j.apsb.2025.02.003","DOIUrl":"10.1016/j.apsb.2025.02.003","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in <em>Ampelopsis grossedentata</em> (<em>A. grossedentata</em>), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^−/−) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM’s anti-AAA action is linked to heme oxygenase (HO)-1 (<em>Hmox-1</em> for the rodent gene) and hypoxia-inducible factor (HIF)-1<em>α</em> in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific <em>Hmox1</em> knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of <em>Hmox-</em>1 by triggering the nuclear translocation and activation of HIF-1<em>α</em>, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1514-1534"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776319","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":"Revolutionizing tuberculosis treatment: Breakthroughs, challenges, and hope on the horizon","authors":"Martin Kufa ,&nbsp;Vladimir Finger ,&nbsp;Ondrej Kovar ,&nbsp;Ondrej Soukup ,&nbsp;Carilyn Torruellas ,&nbsp;Jaroslav Roh ,&nbsp;Jan Korabecny","doi":"10.1016/j.apsb.2025.01.023","DOIUrl":"10.1016/j.apsb.2025.01.023","url":null,"abstract":"<div><div>Tuberculosis (TB), an infectious disease caused by the bacterium <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>), was responsible for the deaths of approximately 1.3 million people in 2022. In addition, 7.5 million new cases of TB have been reported. Present-day treatments require a daily dosing of a multiple-drug regimen for a minimum of six-month, but poor adherence and other factors often lead to treatment failure. Consequently, drug-resistant TB strains have become a growing concern, leading to more complex and expensive treatments. Promising drugs such as bedaquiline, delamanid, and pretomanid have been recently released, and 19 drug candidates are currently at different phases of clinical trials, addressing the problem of drug-resistant TB. Notwithstanding recent advances, the development of effective and safe drugs with novel mechanisms of action remains a challenge due to the unique nature of <em>Mtb</em>. Despite the persistent need for new treatments, TB research remains underfunded, highlighting the importance of collaborations between academia and the private sector in the advancement of anti-TB drug development. This review provides a perspective on the dynamic landscape of anti-TB drug discovery in recent years, offering hope for a more effective approach to combat this persistent global health threat.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1311-1332"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776902","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":"CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer","authors":"Yuncheng Bei ,&nbsp;Sijie Wang ,&nbsp;Rui Wang ,&nbsp;Owais Ahmad ,&nbsp;Meng Jia ,&nbsp;Pengju Yao ,&nbsp;Jianguo Ji ,&nbsp;Pingping Shen","doi":"10.1016/j.apsb.2024.12.019","DOIUrl":"10.1016/j.apsb.2024.12.019","url":null,"abstract":"<div><div>Glucose-6-phosphate dehydrogenase (G6PD), the first rate-limiting enzyme of the pentose phosphate pathway (PPP), is aberrantly activated in multiple types of human cancers, governing the progression of tumor cells as well as the efficacy of anticancer therapy. Here, we discovered that cyclin-dependent kinase 5 (CDK5) rewired glucose metabolism from glycolysis to PPP in breast cancer (BC) cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress. Mechanistically, CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers. More importantly, CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens. Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation, attenuated tumor growth and metastasis, and synergistically sensitized BC cells to poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, in xenograft mouse models. Collectively, our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1608-1625"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776325","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":"USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3","authors":"Yanghao Chen ,&nbsp;Bozhi Ye ,&nbsp;Diyun Xu ,&nbsp;Wante Lin ,&nbsp;Zimin Fang ,&nbsp;Xuefeng Qu ,&nbsp;Xue Han ,&nbsp;Wu Luo ,&nbsp;Chen Chen ,&nbsp;Weijian Huang ,&nbsp;Hao Zhou ,&nbsp;Gaojun Wu ,&nbsp;Yi Wang ,&nbsp;Guang Liang","doi":"10.1016/j.apsb.2024.12.033","DOIUrl":"10.1016/j.apsb.2024.12.033","url":null,"abstract":"<div><div>Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1643-1658"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776389","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":"Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis","authors":"Kaifeng Wang ,&nbsp;Zhixian Lan ,&nbsp;Heqi Zhou ,&nbsp;Rong Fan ,&nbsp;Huiyi Chen ,&nbsp;Hongyan Liang ,&nbsp;Qiuhong You ,&nbsp;Xieer Liang ,&nbsp;Ge Zeng ,&nbsp;Rui Deng ,&nbsp;Yu Lan ,&nbsp;Sheng Shen ,&nbsp;Peng Chen ,&nbsp;Jinlin Hou ,&nbsp;Pengcheng Bu ,&nbsp;Jian Sun","doi":"10.1016/j.apsb.2025.01.017","DOIUrl":"10.1016/j.apsb.2025.01.017","url":null,"abstract":"<div><div>Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case–control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells <em>in vitro</em> at a physiological concentration and prevent the occurrence of HCC <em>in vivo</em> without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of <em>KLF6</em> gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in <em>KLF6/p21</em> expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1383-1396"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776844","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":"Establishment of interpretable cytotoxicity prediction models using machine learning analysis of transcriptome features","authors":"You Wu ,&nbsp;Ke Tang ,&nbsp;Chunzheng Wang ,&nbsp;Hao Song ,&nbsp;Fanfan Zhou ,&nbsp;Ying Guo","doi":"10.1016/j.apsb.2025.02.009","DOIUrl":"10.1016/j.apsb.2025.02.009","url":null,"abstract":"<div><div>Cytotoxicity, usually represented by cell viability, is a crucial parameter for evaluating drug safety <em>in vitro</em>. Accurate prediction of cell viability/cytotoxicity could accelerate drug development in the early stage. In this study, by integrating cellular transcriptome and cell viability data using four machine learning algorithms (support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM)) and two ensemble algorithms (voting and stacking), highly accurate prediction models of 50% and 80% cell viability were developed with area under the receiver operating characteristic curve (AUROC) of 0.90 and 0.84, respectively; these models also showed good performance when utilized for diverse cell lines. Concerning the characterization of the employed Feature Genes, the models were interpreted, and the mechanisms of bioactive compounds with a narrow therapeutic index (NTI) can also be analyzed. In summary, the models established in this research exhibit superior capacity to those of previous studies; these models enable accurate high-safety substance screening <em>via</em> cytotoxicity prediction across cell lines. Moreover, for the first time, Cytotoxicity Signature (CTS) genes were identified, which could provide additional clues for further study of mechanisms of action (MOA), especially for NTI compounds.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1344-1358"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776904","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":"Intravenous delivery of STING agonists using acid-sensitive polycationic polymer-modified lipid nanoparticles for enhanced tumor immunotherapy","authors":"Ying He ,&nbsp;Ke Zheng ,&nbsp;Xifeng Qin ,&nbsp;Siyu Wang ,&nbsp;Xuejing Li ,&nbsp;Huiwen Liu ,&nbsp;Mingyang Liu ,&nbsp;Ruizhe Xu ,&nbsp;Shaojun Peng ,&nbsp;Zhiqing Pang","doi":"10.1016/j.apsb.2024.06.004","DOIUrl":"10.1016/j.apsb.2024.06.004","url":null,"abstract":"<div><div>Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1211-1229"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141392949","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":"Remodeling tumor immunosuppressive microenvironment through dual activation of immunogenic panoptosis and ferroptosis by H2S-amplified nanoformulation to enhance cancer immunotherapy","authors":"Yingli Luo ,&nbsp;Maoyuan Linghu ,&nbsp;Xianyu Luo ,&nbsp;Dongdong Li ,&nbsp;Jilong Wang ,&nbsp;Shaojun Peng ,&nbsp;Yinchu Ma","doi":"10.1016/j.apsb.2024.12.014","DOIUrl":"10.1016/j.apsb.2024.12.014","url":null,"abstract":"<div><div>The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy. Consequently, a nanoformulation containing metal sulfide of FeS and GSDMD plasmid (NP_FeS/GD) had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis, as well as reprogramming immunosuppressive effects <em>via</em> H₂S amplification. The bioactive NP_FeS/GD exhibited controlled release of GSDMD plasmid, H₂S, and Fe²⁺ in response to the tumor microenvironment. Fe²⁺, H₂S, and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis. Furthermore, releasing H₂S could mitigate the overexpression of indoleamine 2,3-dioxygenase1 (IDO1) induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1. Consequently, NP_FeS/GD effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition. This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H₂S gas therapy for enhancing tumor immunotherapy, offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1242-1254"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776316","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":"STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation","authors":"Chengfei Zhang ,&nbsp;Ping Xu ,&nbsp;Yongsheng Wang ,&nbsp;Xin Chen ,&nbsp;Yue Pan ,&nbsp;Zhijie Ma ,&nbsp;Cheng Wang ,&nbsp;Haojun Xu ,&nbsp;Guoren Zhou ,&nbsp;Feng Zhu ,&nbsp;Hongping Xia","doi":"10.1016/j.apsb.2024.12.034","DOIUrl":"10.1016/j.apsb.2024.12.034","url":null,"abstract":"<div><div>Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1535-1551"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776317","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}