Acta Pharmaceutica Sinica. B最新文献

{"title":"Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies","authors":"Hongyan Zhan,&nbsp;Ruifang Zheng,&nbsp;Yanyan Li,&nbsp;Xinyu Liu,&nbsp;Yujie Shi,&nbsp;Ruxuan Chen,&nbsp;Qi Hou,&nbsp;Hui Huang,&nbsp;Mingbao Lin","doi":"10.1016/j.apsb.2026.06.034","DOIUrl":"10.1016/j.apsb.2026.06.034","url":null,"abstract":"<div><div>Telomeres and telomerase have been extensively implicated in the cellular processes of aging and inflammation. Recent studies have shown that telomere length (TL), the shelterin complex, and telomerase dysfunction are closely related to non-malignant pulmonary diseases, including interstitial lung diseases (ILD), chronic obstructive pulmonary disease (COPD), and asthma. Short telomere defects with or without mutations in telomere maintenance genes and telomerase are relatively common, affecting the progression of non-malignant pulmonary diseases, explaining disease susceptibility, and revealing clinically relevant manifestations. In this review, we examine the biological characteristics and functions of telomeres and telomerase, and investigate the intricate relationship between changes in TL and mutations in telomerase genes in non-malignant pulmonary diseases after a detailed associated literature review. Subsequently, we focus on the clinical features of non-malignant pulmonary diseases related to dysfunctional telomeres/telomerase, as well as the potential molecular mechanisms underlying these associations, along with the current status of therapeutic interventions. Finally, we delineate current knowledge gaps and transformative opportunities in telomere biology research, with a focus on bridging molecular discoveries to clinical innovations for telomere-associated non-malignant pulmonary diseases, aiming to accelerate the development of precision diagnostic tools and mechanism-based therapeutics.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 4829-4853"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720707","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":"Exendin-4 alleviates anxiety-like behaviors in chronic restraint stress mice via regulating BLA GLP-1R/BDNF signaling","authors":"Ke Wei,&nbsp;Meng Yu,&nbsp;Lei Gao,&nbsp;Qiaoyue Zhang,&nbsp;Jianhua Ding,&nbsp;Qian Zhang,&nbsp;Gang Hu","doi":"10.1016/j.apsb.2026.05.031","DOIUrl":"10.1016/j.apsb.2026.05.031","url":null,"abstract":"<div><div>Clinical studies have suggested that exendin-4 (Ex-4) exhibits therapeutic potential for anxiety disorders, yet the molecular mechanisms underlying its efficacy remain largely unclear. Our study demonstrates that Ex-4 at specific doses ameliorates anxiety-like behaviors in mice. Mechanistically, Ex-4 could cross the blood–brain barrier and enter the central nervous system, where it exerts anxiolytic effects by activating glucagon-like peptide-1 receptor (GLP-1R) in the basolateral amygdala (BLA). Anterior dorsal bed nucleus of the stria terminalis (adBNST) as a downstream projection target of BLA neurons. Chemogenomic inhibition of the BLA-adBNST circuit induced anxiety-like phenotypes, which were rescued by Ex-4 treatment. Brain-derived neurotrophic factor (BDNF), a critical neurotrophin implicated in neuropsychiatric disorders including anxiety and depression, was functionally interrogated in this pathway. Furthermore, conditional knockdown of <em>Bdnf</em> in the BLA-adBNST circuit abolished the anxiolytic effects of Ex-4, indicating that the activation of GLP-1R in BLA neurons drives BDNF release into adBNST to mitigate anxiety. Taken together, these studies identify a central mechanism whereby Ex-4 attenuates anxiety-like behaviors by promoting BDNF release in the BLA-adBNST circuit.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5168-5182"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719551","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":"Universal off-the-shelf TGF-β1-knockout whole-tumor cell vaccine overcomes immunotherapy resistance in pMMR/MSS tumors","authors":"Weixiao Yang,&nbsp;Zhexu Dong,&nbsp;Qi Xiong,&nbsp;Yushuang Ren,&nbsp;Lin Zhang,&nbsp;Yi Liu,&nbsp;Jiaqi Han,&nbsp;Tian Tian,&nbsp;Xiaolan Su,&nbsp;Gang Shi,&nbsp;Hongxin Deng","doi":"10.1016/j.apsb.2026.06.001","DOIUrl":"10.1016/j.apsb.2026.06.001","url":null,"abstract":"<div><div>Mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) tumors, representing the majority of solid cancers, remain largely unresponsive to immune checkpoint inhibitors, highlighting the urgent need for effective therapeutic strategies. Tumor cell vaccines, serving as delivery platforms for a broad repertoire of tumor antigens, hold potential for eliciting systemic antitumor immunity, yet their clinical efficacy has remained limited. Here, we developed T<em>β</em>1KO/PolyIC-Vac, an off-the-shelf therapeutic whole-tumor cell vaccine generated by CRISPR-Cas9-mediated TGF-<em>β</em>1 knockout and formulated with the TLR3 agonist Poly(I:C). In therapeutic vaccination models, subcutaneous vaccination significantly suppressed distal tumor growth, reduced lung metastases, and delayed spontaneous colorectal tumor progression. It also synergized with anti-PD-1 blockade, enhancing complete response rates and establishing baseline antitumor immunity. Mechanistically, knockout of tumor-derived TGF-<em>β</em>1 reprogrammed immunity by reducing MDSC accumulation to relieve local immunosuppression and activate dendritic cells in draining lymph nodes, while intrinsically triggering the tumor STAT1–IL-15 axis to enhance vaccine immunogenicity. Poly(I:C) further enhanced cross-presentation and adaptive immunity, conferring long-term cross-protection against heterologous tumors. Together, these findings establish T<em>β</em>1KO/PolyIC-Vac as a universal tumor vaccine platform capable of efficiently delivering a comprehensive repertoire of tumor antigens and eliciting robust, durable, and cross-protective tumor-specific immunity in immunotherapy-resistant pMMR/MSS tumors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5405-5423"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719656","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":"Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells","authors":"Yuqin Tan,&nbsp;Jiaojiao Zheng,&nbsp;Ruojiao Wang,&nbsp;Zhaozhong Zhong,&nbsp;Suxiang Chen,&nbsp;Shuo Lu,&nbsp;Jiayu Zheng,&nbsp;Yongrong Ye,&nbsp;Ning Na,&nbsp;Tong Zheng","doi":"10.1016/j.apsb.2026.05.020","DOIUrl":"10.1016/j.apsb.2026.05.020","url":null,"abstract":"<div><div>Renal fibrosis induces irreversible renal failure and lacks therapies. The tubular epithelial cells (TEC) largely depend on exosomes to create a pro-fibrotic microenvironment, initiating fibroblast activation. However, how exosome secretion of TEC is over-activated during renal fibrogenesis remains unknown. Herein, <em>in vitro</em> high-throughout screen uncovered acetyltransferase NAT10 as promising target to interfere with TEC-fibroblast communication. Further experiments showed that NAT10 was upregulated mainly in the TEC of fibrotic kidneys, and its conditional depletion in TEC alleviated renal fibrosis <em>in vivo</em>. Mechanistically, nuclear NAT10 coordinated with cytoplasmic NAT10 to promote exosome secretion of TEC to induce fibroblast activation <em>via</em> combining mRNA ac4C modification and lysine acetylation (Kac). Moreover, NAT10 upregulated the abundance of exosomal Gli in TEC, which were vital for fibroblast activation. In summary, NAT10-mediated orchestration of ac4C and Kac modifications is the mechanism of over-activated exosome secretion of TEC during renal fibrogenesis. And targeting NAT10 with Remodelin is a promising therapy for renal.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5328-5350"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719541","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":"Phase change nanodroplets: Challenges and clinical potential","authors":"Xiaoyu Wang,&nbsp;Roman Barmin,&nbsp;Roger Molto Pallares,&nbsp;Anne Rix,&nbsp;Fabian Kiessling","doi":"10.1016/j.apsb.2026.05.030","DOIUrl":"10.1016/j.apsb.2026.05.030","url":null,"abstract":"<div><div>Phase change nanodroplets (PCND) consist of a liquid fluorocarbon core, which vaporizes into gas upon energy excitation, and a stabilizing shell. Through this phase-change property, PCND combine nanoparticle-like stability and pharmacokinetics, such as tissue extravasation and uptake by the mononuclear phagocyte system, with distinctive microbubble-like capabilities, namely ultrasound contrast enhancement and energy-triggered therapeutic action. PCND serve both as highly sensitive imaging agents, from molecular imaging to high-resolution vascular mapping, and as versatile therapeutics, used for example for thrombolysis, tissue ablation, biofilm removal, immunomodulation, and drug delivery. This review article provides a focused review of the biological behavior of PCND, including blood half-life, biodistribution, clearance pathways, and tumor accumulation, following a brief overview of the key physicochemical features that shape their <em>in vivo</em> fate. By comparing data across studies, we identify major inconsistencies in reported pharmacokinetics and highlight critical knowledge gaps, particularly regarding safety data. We further summarize advances in PCND-enabled imaging and therapy, and propose strategies to strengthen formulation design, biological evaluation, and stimulation protocols to support future clinical translation. Overall, PCND hold strong potential as a versatile theranostic platform. Continued systematic and clinically focused research is expected to accelerate their path toward clinical translation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 4998-5015"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719755","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":"Metal-drug coordinated nanozymes for ROS scavenging and Kupffer cell polarization to alleviate drug-induced liver injury","authors":"Xiayun Chen,&nbsp;Ziqi Liang,&nbsp;Lichong Lu,&nbsp;Zhouchuan Shao,&nbsp;Wenhui Tang,&nbsp;Yiqi Liu,&nbsp;Jianqiao Li,&nbsp;Baizhong Chen,&nbsp;Enping Lai,&nbsp;Guodong Zheng,&nbsp;Minyan Wei,&nbsp;Shiying Li","doi":"10.1016/j.apsb.2026.05.006","DOIUrl":"10.1016/j.apsb.2026.05.006","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) is a predominant cause of acute liver failure, intricately associated with excessive reactive oxygen species (ROS) production and the activation of inflammatory cascades. In this study, a metal–drug coordinated nanozyme (M-dCNs) is rationally designed to simultaneously scavenge ROS and polarize Kupffer cells to alleviate DILI. Specifically, the coordination between ferric ions (Fe³⁺) and the complementary therapeutic agents of hesperetin (HST) and KPLH (KPLH1130) facilitates the formation of M-dCNs with uniform particle distribution and enhances structural stability. Notably, M-dCNs exhibits intrinsic antioxidant enzyme-mimetic activity, efficiently neutralizing intracellular ROS in damaged hepatocytes and thereby disrupting apoptosis-related signaling pathways. In parallel, M-dCNs synergistically reprograms hepatic macrophages toward an anti-inflammatory phenotype, leading to a marked reduction in pro-inflammatory cytokines such as tumor necrosis factor <em>α</em> (TNF-<em>α</em>) and interleukin 1<em>β</em> (IL-1<em>β</em>), and ultimately suppressing inflammatory cascades. <em>In vivo</em> studies demonstrate the hepatoprotective potential and therapeutic efficacy of M-dCNs in attenuating oxidative stress, reducing inflammatory cell infiltration, and restoring liver function. Collectively, this work presents a promising strategy for the treatment of DILI <em>via</em> the concurrent modulation of redox homeostasis and inflammatory microenvironment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5471-5486"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720641","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":"Optimizing pyrazine-2-carboxamide derivatives as dual FLT3/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential","authors":"Yingjie Chang,&nbsp;Xue Li,&nbsp;Huirui Wang,&nbsp;Huajun Zhao,&nbsp;Yue Zhou,&nbsp;Wenchao Bi,&nbsp;Ruixue Cheng,&nbsp;Yuxin Shi,&nbsp;He Weng,&nbsp;Xinying Yang,&nbsp;Wei Zhao,&nbsp;Hao Fang,&nbsp;Xuben Hou","doi":"10.1016/j.apsb.2026.05.025","DOIUrl":"10.1016/j.apsb.2026.05.025","url":null,"abstract":"<div><div>Dual FLT3/HDAC inhibition represents a promising synergistic strategy to address tumor heterogeneity. Building upon our prior lead <strong>25h</strong>, we developed novel 6-ethylpyrazine-2-carboxamide derivatives <em>via</em> systematic structural optimization to enhance pharmacokinetic properties and target selectivity. The optimized compound, CF-2-17, demonstrated potent dual inhibition of FLT3 (IC₅₀ = 1.1 nmol/L) and HDACs (IC₅₀ = 9.6 nmol/L), and exhibited a 27-fold selectivity for HDAC1 over HDAC6. Its improved physicochemical properties, including enhanced solubility and metabolic stability, translated into favorable plasma exposure <em>in vivo</em>. In the MOLM-13 (FLT3-ITD) xenograft model, oral administration of CF-2-17 showed antitumor efficacy comparable to combination therapy, without observable toxicity. CF-2-17 also exhibited antiproliferative activity against non-FLT3-ITD hematological malignancies and solid tumors, outperforming single-target agents. Furthermore, CF-2-17 effectively remodeled the tumor immune microenvironment through CD4⁺ T cell activation and IFN-<em>γ</em> elevation, achieving 87% tumor growth inhibition in LLC syngeneic models. Mechanistically, CF-2-17 reversed FLT3 blockade-induced DC dysfunction <em>via</em> activation of the NF-<em>κ</em>B pathway, thereby reinstating DC-mediated antitumor immunity. This dual FLT3/HDAC inhibitor demonstrates synergistic epigenetic-immune modulation, offering a promising approach for heterogeneous malignancies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5383-5404"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722611","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":"Loss of TET2 sulfhydration results in destabilization of TET2 and down-regulation of the immune response in melanoma","authors":"Di Wang,&nbsp;Weiwei Deng,&nbsp;Yang Xie,&nbsp;Ansheng Xie,&nbsp;Yuan Chang,&nbsp;Shuheng Li,&nbsp;Yishan Chen,&nbsp;Leiqiong Gao,&nbsp;Yan Zhang,&nbsp;Zhiying Yu,&nbsp;Bocheng Wang,&nbsp;Yingping Xu,&nbsp;Haijing Wu,&nbsp;Yan Ding,&nbsp;Bin Yang,&nbsp;Lian Zhang,&nbsp;Yunsheng Liang","doi":"10.1016/j.apsb.2026.04.010","DOIUrl":"10.1016/j.apsb.2026.04.010","url":null,"abstract":"<div><div>Loss of TET2 protein leads to reduced DNA 5-hydroxymethylation (5-hmC), a key epigenetic alteration in melanoma, yet the regulatory mechanism governing TET2 stability remains unclear. Here, TET2 sulfhydration was analyzed in clinical melanoma samples, with sulfhydration sites identified by mass spectrometry, and the effects of active sulfur on TET2 stability, catalytic activity, and global 5-hmC assessed in melanoma cells. TET2 sulfhydration was significantly depleted in melanoma and further reduced in advanced stages. The cysteine-rich zinc finger domain at C1186/1202 was identified as the key sulfhydration site, which is essential for maintaining TET2 stability and enzymatic activity. Active sulfur restored TET2 sulfhydration, up-regulated TET2 protein, and reprogrammed global DNA hydroxymethylation. Notably, active sulfur synergized with anti-PD-1 therapy by enhancing IFN-<em>γ</em>-induced Th1-type chemokine and MHC-I expression in melanoma cells, thereby boosting CD8⁺ T-cell-mediated immune responses. These findings demonstrate that TET2 sulfhydration at C1186/1202 is a crucial post-translational modification for TET2 stability and function, playing a key role in epigenetic regulation and antitumor immunity, and highlight the immunoadjuvant potential of reactive sulfur species in melanoma immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5183-5199"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721296","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":"Novel noscapine derivative induces AML differentiation by dual-engaging DHODH and mitochondrial lipids to trigger a metabolic–epigenetic–transcriptional cascade","authors":"Shuting Shen,&nbsp;Defeng Li,&nbsp;Youping Zhang,&nbsp;Shiwei Li,&nbsp;Lei Li,&nbsp;Wenhao Shen,&nbsp;Yujie Ma,&nbsp;Wenhao Zhang,&nbsp;Rong Tao,&nbsp;Wei Wang,&nbsp;Biao Jiang,&nbsp;Fang Bai,&nbsp;Chuanxu Liu,&nbsp;Yongqiang Zhang,&nbsp;Qianqian Yin","doi":"10.1016/j.apsb.2026.05.019","DOIUrl":"10.1016/j.apsb.2026.05.019","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is a heterogeneous and devastating hematologic malignancy characterized by differentiation blockage and immature progenitor accumulation, positioning differentiation therapy as a promising therapeutic strategy. However, clinical success is largely confined to acute promyelocytic leukemia (APL) and isocitrate dehydrogenase (IDH)-mutated AML, leaving most AML subtypes with unmet needs. Herein, novel noscapine derivative ES428 is discovered that induces AML differentiation and exhibits potent anti-AML efficacy across diverse AML cell lines, primary patient samples, as well as cell line- and patient-derived xenograft models. Target deconvolution with combinatorial strategies identifies dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in <em>de novo</em> pyrimidine synthesis, as the direct functional target. Integration of molecular dynamics simulations and comprehensive structure-activity relationship studies elucidates ES428’s unique mechanism <em>via</em> simultaneous engagement with DHODH and mitochondrial membrane lipids. This dual-engagement underpins ES428’s enhanced target engagement, efficacy, and selectivity in physiologically relevant mitochondrial membrane environment, potentially through stabilizing ES428-DHODH interaction <em>in situ</em> and facilitating ES428’s selective mitochondrial localization. Furthermore, ES428 triggers a mechanistic cascade linking decreased pyrimidine synthesis, reduced O-linked <em>N</em>-acetylglycosylation (O-GlcNAcylation), EP300/CREBBP catalytic inhibition, and transcriptional reprogramming. Our findings identify promising lead candidates, establish a novel DHODH-targeting strategy, and provide important mechanistic insights to advance differentiation therapies for myeloid malignancies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5363-5382"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727856","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":"H2AC19 promotes lung adenocarcinoma progression via p300/EGR1/MMP-1-mediated angiogenesis","authors":"Fuwen Zuo,&nbsp;Jinlong Yu,&nbsp;Tong Liu,&nbsp;Xiaorui Liu,&nbsp;Jilong Yin,&nbsp;Pengzhong Ding,&nbsp;Yuhan Pang,&nbsp;Zhengdong Luo,&nbsp;Xiaofeng Wang,&nbsp;Ling Guo,&nbsp;Yirong Zhang,&nbsp;Shuang Qi,&nbsp;Lutao Du,&nbsp;Ziying Wang,&nbsp;Fan Yi,&nbsp;Xiaoshi Zhang","doi":"10.1016/j.apsb.2026.07.010","DOIUrl":"10.1016/j.apsb.2026.07.010","url":null,"abstract":"<div><div>Angiogenesis is a hallmark of lung adenocarcinoma (LUAD) and a leading cause of mortality. Identifying potential therapeutic targets that modulate this process is of critical clinical importance. Here, we established a 12-gene risk-scoring model through bioinformatics screening and systematically delineated the molecular function of H2AC19, a previously poorly understood histone variant within this signature. Analysis of human LUAD specimens revealed elevated H2AC19 expression, which correlated positively with angiogenesis markers and advanced clinical stage and negatively with patient prognosis. Functional validation using CRISPR/Cas9 in patient-derived organoids (PDOs), <em>in vitro</em> cell models and <em>in vivo</em> xenografts demonstrated that H2AC19 promotes angiogenesis and tumor growth. Mechanistically, H2AC19 recruits p300 through its amino acid residues 24–88 to specifically augment H3K27 acetylation at the EGR1 promoter region, thereby triggering EGR1 transcriptional activation and subsequently promoting MMP-1-driven angiogenesis and progression of LUAD. Furthermore, we evaluated the therapeutic potential of lipid nanoparticles (LNP)-encapsulated siRNA targeting H2AC19, which significantly suppressed angiogenesis and LUAD progression. Collectively, our findings establish a critical role for H2AC19 in governing angiogenesis and highlight its potential as a promising therapeutic target for LUAD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 8","pages":"Pages 5070-5085"},"PeriodicalIF":14.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719440","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}