Acta Pharmacologica Sinica最新文献

{"title":"CYFIP2 deficiency ameliorates renal interstitial fibrosis through attenuating tubular senescence in hypertensive nephropathy.","authors":"Ming-Chen Sun, Fu-Wen Zuo, You-Zhao Wang, Xiu-Li Ren, Hong-Shen Lu, Ming-Bo Zheng, Hao-Ran Zhang, Han-Lin Liu, Cui-Cui Lu, Cheng-Wu Shen, Ji-Chao Wu","doi":"10.1038/s41401-026-01793-x","DOIUrl":"https://doi.org/10.1038/s41401-026-01793-x","url":null,"abstract":"<p><p>Tubulointerstitial fibrosis is the central pathological feature of hypertensive nephropathy, with cellular senescence being a key driver. Therefore, identifying therapeutic targets in senescent renal tubular epithelial cells is clinically important. The cytoplasmic FMR1-interacting protein (CYFIP) family, which comprises two evolutionarily conserved members, CYFIP1 and CYFIP2, plays crucial roles in neurological regulation. CYFIP2, a key member, is implicated in cytoskeletal dynamics and apoptosis within the nervous system; however, its renal expression pattern and function remain undefined. This study revealed that CYFIP2 expression was significantly upregulated in the renal cortex, particularly in the proximal tubules, of DOCA/salt-induced hypertensive mice, and was positively correlated with the extent of fibrosis. Consistently, CYFIP2 was highly expressed in the renal tubules of patients with hypertensive nephropathy, where its level inversely correlated with the estimated glomerular filtration rate (eGFR). Tubule-specific deletion of CYFIP2 attenuated hypertension-induced cellular senescence (reduced SA-β-gal, p53/p21, and SASP; increased Klotho) and mitigated renal dysfunction, collagen deposition, and epithelial‒mesenchymal transition (EMT). In vitro, CYFIP2 silencing alleviated TGF-β1-induced senescence and fibrosis in HK-2 cells. Mechanistically, CYFIP2 and p53 formed a positive feedback loop that promoted fibrosis by inhibiting the Hippo pathway and enhancing YAP nuclear translocation. The p53 agonist Nutlin-3a reversed the protective effect of CYFIP2 knockout, while the inhibitor Pifithrin-α mimicked this effect. These findings underscore the pivotal role of the CYFIP2/p53-Hippo/YAP axis in hypertensive renal injury, and identify CYFIP2 as a potential therapeutic target. CYFIP2/p53-Hippo signaling drives tubular senescence and renal fibrosis in hypertensive nephropathy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832105","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":"Trim47 protects against hypoxic-ischaemic brain injury in neonatal rats by reducing brain microvascular endothelial inflammation and BBB disruption by interacting with ZO1.","authors":"Xiao-Hui Kong, Zu-Bin Zhang, Yu Kong, Da-Man Tu, Qian-Qian Li, Chen-Xi Feng, Xin Ding, Li-Xiao Xu, Gen Li, Tao Pan, Zheng-Hong Qin, Bin Sun, Xing Feng, Mei Li","doi":"10.1038/s41401-026-01783-z","DOIUrl":"https://doi.org/10.1038/s41401-026-01783-z","url":null,"abstract":"<p><p>Hypoxic-ischaemic (HI) brain damage is the main contributor to neonatal brain damage and neurodevelopmental impairments. The E3 ubiquitin ligase tripartite motif 47 (Trim47) plays pivotal roles in regulating inflammation, autophagy, and apoptosis in the pathological processes of various diseases. However, the role of Trim47 in neonatal HI brain injury remains unknown. In vivo and in vitro models of neonatal rat brain HI and OGD/R-treated brain microvascular endothelial cells were established to investigate the roles of Trim47 and its underlying regulatory mechanism in neonatal brain injury. We found that Trim47 was highly expressed in brain microvascular endothelial cells, astrocytes and microglia and was downregulated in brain microvascular endothelial cells after neonatal HI injury in vivo and in vitro. Trim47 overexpression attenuated neonatal brain injury and blood-brain barrier (BBB) disruption following HI injury. It also improved long-term neurological outcomes and brain atrophy after HI injury. Trim47 overexpression increased the expression of the tight junction proteins ZO1 and occludin and suppressed MMP9 and AQP4 expression in brain microvascular endothelial cells after OGD/R. It also improved BBB function through ubiquitin conjugation to ZO1 and attenuated brain microvascular endothelial inflammation by suppressing NF-κB activation after OGD/R. However, Trim47 knockdown had the opposite effects. Thus, the present study demonstrates that the neuroprotective role of Trim47 in brain damage is achieved by preserving BBB function through interaction with ZO1 and by reducing brain microvascular endothelial inflammation through the suppression of NF-κB activation after neonatal HI injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832150","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":"PACSIN2-mediated synaptic injury contributes to behavioral disorders caused by chronic stress.","authors":"Chang-Min Wang, Ye Li, Yu-Hang Yi, Xiao Chen, Tian Lan, Hai-Yan Lou, Wen-Cheng Jian, Mei-Jian Wang, Shu-Yan Yu","doi":"10.1038/s41401-026-01790-0","DOIUrl":"https://doi.org/10.1038/s41401-026-01790-0","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is generally associated with synaptic damage in specific brain regions. However, the molecular mechanisms underlying the pathogenesis of MDD remain largely unknown. In the present study, we demonstrate that chronic stress-an established inducer of depression-like behaviors in animal models-upregulates the expression of protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2) in the hippocampal dCA1 region, a key regulator of the actin cytoskeleton and endocytic processes. The overexpression of PACSIN2 in CA1 hippocampal pyramidal neurons may increase the susceptibility to stress stimulation in rats through physical interactions with dynamin and cooperative modulation of the expression of postsynaptic membrane GluA1 AMPA receptors. Selective knockdown of PACSIN2 in the dCA1 hippocampal region of depressed rats significantly enhanced synaptic transmission, ultimately ameliorating depression-like behaviors. These findings provide direct evidence that abnormal function of hippocampal neurons resulting from perturbations in neuroplasticity may be involved in the pathogenesis of MDD. Moreover, PACSIN2 may serve as one of the underlying molecular controls through which chronic stress induces synaptic loss and dysfunction and the resulting behavioral disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832210","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":"TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.","authors":"Yan-Yan Li, Jian-Rong Yuan, Jie Tang, Lei Chen, Jun-Chao Wu, Zheng-Hong Qin, Rui Sheng","doi":"10.1038/s41401-026-01751-7","DOIUrl":"https://doi.org/10.1038/s41401-026-01751-7","url":null,"abstract":"<p><p>Oxidative stress and inflammation play pivotal roles in the secondary brain injury following intracerebral hemorrhage (ICH). Our previous study on cerebral ischemia showed that TIGAR interacted directly with ATF4, thereby suppressing ATF4-mediated endoplasmic stress. In this study, we investigated whether TIGAR conferred protection against ICH by mitigating oxidative stress and inflammation and the regulatory mechanisms. ICH mouse model was established by microinjection of collagenase VII into the right striatum. Neurological dysfunction score was assessed at 24 h and 72 h post-ICH, and mice were sacrificed and the brains were collected at 72 h post-ICH. We found a significant elevation in TIGAR protein expression in the striatum of ICH mice with increased distribution of TIGAR protein among neurons, microglia and astrocytes. Deletion of TIGAR exacerbated neurological deficits and increased hematoma volume. Conversely, overexpression of TIGAR effectively mitigated neurological deficits, reduced hematoma volume and improved neuronal damage in ICH mice. We demonstrated that TIGAR overexpression significantly attenuated lipid peroxide 4-HNE as well as malondialdehyde content (a lipid oxidation product), while suppressing ROS production. In addition, TIGAR overexpression inhibited NLRP3 inflammasome expression along with caspase-1 cleavage. Moreover, TIGAR overexpression downregulated mRNA levels of inflammatory cytokines IL-1β and IL-6 while impeding microglial transformation into pro-inflammatory M1 phenotype. Intriguingly, TIGAR overexpression exerted inhibitory effects on the expression and activity of ATF4 and NOX4/p22phox involved in intracellular oxidative stress and inflammation regulation. In ICH mice, administration of NOX inhibitor GLX351322 (5 mg·kg^-1·d^-1, i.p. for 2 days) significantly ameliorated the intracerebral hemorrhage injury exacerbated by TIGAR knockdown. Collectively, we demonstrate upregulation of TIGAR proteins with enhanced distribution among neurons and glial cells post-ICH. TIGAR may alleviate oxidative stress and inflammation by inhibiting the ATF4/NOX4/p22phox signaling pathway, thereby reducing ICH-associated neuronal damage. The role and mechanism of TIGAR in intracerebral hemorrhage injury. TIGAR suppresses the ATF4/NOX4/p22phox axis, thereby reducing the production of reactive oxygen species (ROS), which subsequently alleviates oxidative stress and inflammatory responses to mitigate hemorrhagic injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832197","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":"Nanoparticles for autoimmune diseases: advancing diagnostics and therapeutic solutions.","authors":"Elaine Xue Ning Ong, Chester Yan Jie Ng, Lu-Lei Cao, Xuexin Li, Pan P Li, Nguan Soon Tan, Zehuan Liao, Yan Zhao","doi":"10.1038/s41401-026-01794-w","DOIUrl":"https://doi.org/10.1038/s41401-026-01794-w","url":null,"abstract":"<p><p>Autoimmune diseases pose a significant challenge to modern medicine due to their complicated and poorly understood mechanisms, which hinder effective diagnosis and treatment. The rising global incidence of autoimmune disorders is projected to place increasing strain on healthcare systems and financial resources. In response, nanotechnology has emerged as a promising avenue for both the diagnosis and treatment of these conditions. Among various nano-technological approaches, nanoparticles have garnered particular attention due to their advantageous properties including biocompatibility, enhanced drug bioavailability and efficient permeability across biological membranes. Furthermore, their unique characteristics such as magnetic responsiveness, anti-inflammatory, and antimicrobial capabilities, enable precise drug delivery and improved therapeutic outcomes, as well as the potential for earlier disease detection. Despite these promising developments, the clinical translation of nanoparticle-based strategies faces challenges including concerns regarding their stability in vivo and the need for further research to validate their safety and efficacy. While current diagnostic tools remain limited, certain nanoparticles have already received approval from the US Food and Drug Administration, demonstrating their potential for clinical application. This review aims to highlight the recent advances in use of nanoparticles for the diagnosis and treatment of autoimmune diseases, and to explore their prospective role in future clinical practice.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832108","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":"Discovery of a potent and orally bioavailable type Ⅰ PRMTs inhibitor for triple-negative breast cancer treatment.","authors":"Shu-Yan Zhou, Qiang-Sheng Zhang, Lu Li, Zhi-Hao Liu, Xiang Hu, Xue-Ying Chen, Xiao Li, Zhan-Zhan Feng, Guo-Quan Wan, Luo-Ting Yu","doi":"10.1038/s41401-025-01713-5","DOIUrl":"10.1038/s41401-025-01713-5","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains the most refractory breast cancer subtype because of its high invasiveness, lack of therapeutic targets and heterogeneity. Type I protein arginine methyltransferases (PRMTs) are important epigenetic enzymes that catalyze the methylation of arginine residues in various proteins, playing crucial roles in numerous cellular processes. Targeting type I PRMTs represents a promising strategy for TNBC. In this study we characterized a novel selective type I PRMTs inhibitor, SKLB06489. Compared with the precursor compound SKLB06329 (F = 0.2%), SKLB06489 exhibited a markedly enhanced oral bioavailability (F = 88.4%). SKLB06489 inhibited PRMT1, PRMT6, and PRMT8 with IC₅₀ values of 64.55, 4.21, and 51.27 nM, respectively. In TNBC cell lines MDA-MB-231, Hs578T, and BT549, SKLB06489 dose-dependently inhibited cell proliferation and colony formation with IC₅₀ values in the low micromolar range. In MDA-MB-231 subcutaneous xenograft models, administration of SKLB06489 (40, 80 mg·kg^-1·d^-1, i.g. for 33 days) dose-dependently suppressed tumor growth. RNA sequencing and in vitro validation revealed that SKLB06489 inhibited TNBC proliferation by impairing DNA replication, compromising DNA damage repair, and ultimately inducing G₀/G₁-phase cell cycle arrest and apoptosis. In addition, SKLB06489 (5, 10 μΜ) dose-dependently enhanced intracellular cholesterol efflux in MDA-MB-231 cells and Hs578T cells via upregulation of the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), thereby disrupting cholesterol metabolic homeostasis. We conclude that SKLB06489 is a potent type Ⅰ PRMTs inhibitor with great therapeutic potential and is expected to overcome the TNBC treatment bottleneck. The discovery of SKLB06489-regulated cholesterol homeostasis provides a novel perspective on the biological function of type Ⅰ PRMTs, particularly their role in regulating metabolic pathway.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1285-1299"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987638","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":"A sinomenine derivative protects life-threatening inflammatory injuries via covalently binding to a novel allosteric inhibition site of IRF3.","authors":"Shuo Li, Bing Xu, Ming-Jun Lu, Qian-Wen Wu, Wen-Qing Qin, Zi-Qi Dai, Xiao-Jiao-Yang Li, Jin-Zhao Bai, Hai-Min Lei, Run-Ping Liu","doi":"10.1038/s41401-025-01723-3","DOIUrl":"10.1038/s41401-025-01723-3","url":null,"abstract":"<p><p>The severe inflammation associated with infectious or inflammatory diseases significantly contributes to mortality. Interferon regulatory factor 3 (IRF3) represents a potential anti-inflammatory target, but the development of IRF3 inhibitors has not yielded satisfactory results to date. In this study, we established a phenotype-based high-throughput screening system to conduct activity-guided hierarchical screening of clinical frequently used anti-inflammatory and anti-rheumatic herbal extracts and compounds. Employing a Gaussia-luciferase reporter system driven by the IFNB1 promoter, we identified sinomenine as a potent type I interferon (IFN) inhibitor from a set of 28 anti-inflammatory herbal products. Furthermore, among 24 synthesized sinomenine derivatives modified by various electrophilic groups, Sim-9 (2.5-10 μM) dose-dependently inhibited IFN responses triggered by TLRs, RLRs, and STING activation in mouse RAW264.7 cells and in human THP-1 cells, HT-29 cells and A549 cells. We demonstrated that Sim-9, by covalently binding to Cys222, induced a conformational change in the pLxIS motif-binding surface of IRF3, thus blocking its interaction with upstream adapters, including TRIF, MAVS and STING, and subsequent homodimerization of IRF3 itself, which were all essential for activation of type I IFN responses. In in vivo experiments, we showed that injection of Sim-9 (30, 60 mg/kg, i.p.) effectively protected against devastating inflammation in cecal ligation and puncture (CLP)-induced sepsis in mice, and improved cerulein-induced pancreatitis by inhibiting IRF3. Our study discovers Sim-9 as a novel covalent allosteric inhibitor of IRF3 and reveals that the pLxIS motif binding surface represents a previously uncharacterized druggable target for IRF3 activation, providing a promising therapeutic strategy for the treatment of severe inflammatory injuries.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1233-1248"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987577","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":"PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations.","authors":"Zi-Yang Chen, Ren Guo, Min Wang, Si-Jia Ji, Jing-Wei Zhang, Hui-Xiang Zheng, Shi-Tong Wang, Xin Xie","doi":"10.1038/s41401-025-01711-7","DOIUrl":"10.1038/s41401-025-01711-7","url":null,"abstract":"<p><p>Phospholamban (PLN) is a regulatory protein of the SERCA2α calcium transporter, which plays an important role in maintaining calcium homeostasis in cardiomyocytes. Deletion of the 14th arginine of PLN (PLN-R14del) leads to dysregulation of SERCA2α and PLN aggregation, and is a common cause of dilated cardiomyopathy. In this study, by using CRISPR-Cas9 gene editing technology, we constructed the PLN-R14del mouse model and hESCs. The PLN^{R14del/R14del} mice developed severe ventricular dilation, cardiac fibrosis, and PLN aggregation, as well as premature death due to heart failure. Reduced cardiomyocyte functions and PLN aggregation were also observed in the human PLN^R14del/WT cardiomyocytes differentiated from gene-edited hESCs. AAV delivery of PLN-L31A/I40A, which blocks PLN-R14del and SERCA2α interaction but without blocking the function of the latter, provided a therapeutic effect in both mice and human cardiomyocytes. These results not only suggest that PLN-L31A/I40A gene therapy is practical, but also suggest that blocking the interaction between PLN-R14del and SERCA2α with other modalities, such as small molecules, might also be beneficial.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1191-1203"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987660","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":"Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.","authors":"Ye Peng, Sha-Sha Wang, Ke-Dao Lai, Jun-Rui Ye, Wen-Bing He, Xu Yan, Zhao Zhang, Shi-Feng Chu, Nai-Hong Chen","doi":"10.1038/s41401-025-01709-1","DOIUrl":"10.1038/s41401-025-01709-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a prevalent neurodegenerative dementia, presents therapeutic challenges due to safety concerns about amyloid-targeting strategies. Traditional Chinese medicine (TCM) may offer alternative avenues for exploration. Ginsenoside Rg1, a key bioactive component of ginseng, has shown neuroprotective potential in okadaic acid (OKA)-induced rat model, its limited brain bioavailability suggests that its metabolite protopanaxatriol (Ppt) may exert these effects. In this study, we investigated the therapeutic effects of Ppt on OKA-induced mice model and the underlying mechanisms. Cultured hippocampal neurons were treated with OKA (0.5 nM) with or without Ppt co-treatment for 24 h. We showed that Ppt (1.25-40 nM) exerted dose-dependent neuroprotection against OKA-induced cytotoxicity, with the maximal protection observed at 10 nM. The suppressed tau aggregation by Ppt was confirmed using a Venus-tau bimolecular fluorescence complementation (BiFC) system. Molecular dynamics simulations and microscale thermophoresis (MST) revealed that Ppt bound to the catalytic domain of CDK5 at Cys83, destabilizing the CDK5/p25 complex. Co-immunoprecipitation (Co-IP) assays with CDK5 mutants (S159T, C83A, F80A and D86A) validated this interaction. In vivo mice were treated with Ppt (10 mg/kg, i.g.) for 25 days. On D8 and D9, the mice were bilaterally microinjected with OKA into the cerebral ventricles. We showed that Ppt administration improved spatial memory deficits in Novel Object Recognition and Barnes Maze tests; these effects were abolished in mice expressing a lentivirus-mediated CDK5[C83A] mutant. Hippocampal transcriptomic profiling in OKA-challenged mice following Ppt intervention revealed that Ppt modulated Drp1-mediated mitochondrial fission/fusion dynamics, mitigating OKA-induced mitochondrial homeostasis disruption. Collectively, these results demonstrate that Ppt attenuates tau pathology by selectively targeting CDK5 at Cys83, thereby reducing pathological kinase activity, rebalancing mitochondrial function, and improving cognitive outcomes in an OKA-induced mice neurodegeneration model. The study underscores the therapeutic potential of Ppt in AD treatment and supports CDK5 modulation as a strategic approach for addressing tau-related neurodegeneration.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1132-1148"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016877","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":"Mechanisms, precision therapies, and technological frontiers in coronary atherosclerosis: a comprehensive review.","authors":"Zi-Xuan Qiu, Ruo-Yu Wang, Yi Zhang, Han-Bing Huang, Ruo-Yu He, Hao Yan, Pei-Hua Luo, Bo Yang, Zhi-Fei Xu, Qiao-Jun He","doi":"10.1038/s41401-025-01729-x","DOIUrl":"10.1038/s41401-025-01729-x","url":null,"abstract":"<p><p>Coronary atherosclerosis is a leading cause of morbidity and mortality worldwide and is characterized by complex molecular and cellular mechanisms involving lipid dysregulation, endothelial dysfunction, immune-inflammatory processes, and vascular remodeling. Despite advancements in conventional therapies, including statins and antiplatelet agents, significant residual risk persists, particularly in patients with genetic dyslipidemias, persistent inflammation, or limited access to advanced care. Recent breakthroughs in precision medicine, multiomics technologies, and high-resolution imaging are transforming our approach to cardiovascular risk assessment by enabling refined stratification through single-cell transcriptomics, polygenic risk scoring, and artificial intelligence-powered plaque analysis. This review synthesizes the contemporary understanding of disease mechanisms and emerging therapeutic strategies, highlighting novel interventions targeting PCSK, inflammatory pathways, and vascular regeneration through cell-based therapies. We further explored the transformative potential of CRISPR-Cas9 gene editing for durable lipid lowering, nanotechnology-enabled drug delivery, and gut microbiota modulation targeting metabolites such as trimethylamine N-oxide. Although these innovations promise personalized atherosclerosis management, challenges remain in terms of accessibility, health equity, and clinical implementation. The integration of multimodal data analytics with targeted therapeutics heralds a new era of precision cardiology aimed at reducing the global burden of coronary artery disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1103-1116"},"PeriodicalIF":8.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058262","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}