Acta Pharmaceutica Sinica. B最新文献

{"title":"Neuroprotection by YZG-331 in postoperative cognitive dysfunction via Mg2+-dependent blockade of NMDA receptors","authors":"Han Guo,&nbsp;Jiaojiao Zhao,&nbsp;Keying Tian,&nbsp;Qinghui Guo,&nbsp;Siruan Chen,&nbsp;Yuhan Ge,&nbsp;Wenyan Guo,&nbsp;Xingchen Lin,&nbsp;Hui Bai,&nbsp;Lei Yang,&nbsp;Lei Yang,&nbsp;Xia Qin,&nbsp;Panpan Zhang,&nbsp;Zhanfeng Jia,&nbsp;Ruifang Zheng,&nbsp;Zuxiao Yang,&nbsp;Yun Stone Shi,&nbsp;Dezhi Kong,&nbsp;Tengfei Ji,&nbsp;Wei Zhang","doi":"10.1016/j.apsb.2026.07.025","DOIUrl":"10.1016/j.apsb.2026.07.025","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a debilitating neurological complication that occurs following surgery, for which no effective interventions are currently available. Here, we identified YZG-331, a novel adenosine analog, as a promising neuroprotective agent that rescues cognitive deficits and mitigates dendritic spine loss in a murine POCD model. Integrated proteomic profiling and bioinformatics pathway analysis revealed that YZG-331 selectively targets NMDA receptor (NMDAR) signaling. Electrophysiological recordings and living-cell calcium imaging demonstrated that YZG-331 suppressed NMDAR-mediated currents and calcium influx in a dose-dependent manner. Furthermore, Mg²⁺ is required for YZG-331 to inhibit NMDAR activity. YZG-331 disrupts the formation of NMDAR condensates in the presence of Mg²⁺, thereby attenuating NMDAR-mediated excitotoxicity. Our findings establish YZG-331 as a prospective therapeutic candidate for POCD and reveal Mg²⁺-dependent receptor modulation as a novel pharmacological strategy for targeting NMDAR-associated neuropathologies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5995-6012"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940128","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":"Photothermal-driven sequential immunotherapy overcomes resistance to PARP inhibition in Brca1-deficient triple-negative breast cancer","authors":"Zhenyu Xu,&nbsp;Shengyi Wang,&nbsp;Yiyang Cao,&nbsp;Jianing Song,&nbsp;Yinghuan Liu,&nbsp;Rong Zhang,&nbsp;Xulin Tang,&nbsp;Ya Wang,&nbsp;Haodi Wu,&nbsp;Jiasheng Tu,&nbsp;Qian Chen,&nbsp;Chunmeng Sun","doi":"10.1016/j.apsb.2026.07.022","DOIUrl":"10.1016/j.apsb.2026.07.022","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) faces formidable clinical challenges due to target scarcity and a profound immunosuppressive microenvironment, necessitating innovative therapeutic strategies. Although poly ADP-ribose polymerase inhibitors leverage synthetic lethality in <em>BRCA</em>-mutated tumors, their efficacy is subverted by tumor-associated macrophages (TAMs)-driven immunosuppression, and current combinatorial strategies fail to overcome these resistance barriers. To address this, we engineered a thermo-responsive double-layer gel for spatiotemporally coordinated delivery: mild photothermal therapy reprograms TAMs to dismantle immunosuppressive niches, poly ADP-ribose polymerase inhibitors induce immunogenic tumor death releasing damage-associated molecular patterns, and delayed anti-CD47 antibodies release blocks the CD47-signal regulatory protein <em>α</em> axis. In <em>Brca1</em>-deficient TNBC models, this strategy demonstrated: (1) mild photothermal therapy-activated stimulator of interferon genes pathway triggering TAMs repolarization, (2) tumor-derived double-stranded DNA reinforcing the anti-tumor phenotypes, and (3) anti-CD47 antibody-enhanced phagocytosis and T cell activation <em>via</em> antigen cross-presentation. Consequently, this strategy controlled orthotopic/distal tumors and lung metastases by remodeling the immunosuppressive microenvironment. Our work not only unveils a novel mechanism of physical energy-mediated immune modulation but also establishes a paradigm shift for TNBC therapy, from empirical drug combinations to rationally designed spatiotemporal cascades.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6235-6252"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940581","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":"CMTM6 maintains B cell-intrinsic membrane CD40 stability to regulate anti-tumor immunity","authors":"Runqiu Chen,&nbsp;Wenlong Chang,&nbsp;Fanglin Li,&nbsp;Longhua Gu,&nbsp;Chen Chen,&nbsp;Rong Zhang,&nbsp;Zhiying Li,&nbsp;Jianhua Sun,&nbsp;Jing Chen,&nbsp;Likun Gong,&nbsp;Yiru Long","doi":"10.1016/j.apsb.2026.07.017","DOIUrl":"10.1016/j.apsb.2026.07.017","url":null,"abstract":"<div><div>The essential role of B cells and B cell intrinsic molecules in tumor immunity is beginning to be recognized. Tumor cell CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as programmed cell death ligand 1 (PD-L1) and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation, memory B cell differentiation, T/B cell interaction and B cell anti-tumor immune responses. Through multi-omics data mining and B-cell agonist screening, we identified that CMTM6 interacted with CD40 and maintained CD40 membrane levels in B cells. CMTM6 <em>cis</em>-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation. CMTM6 deficiency led to impaired CD40 signaling-mediated B cell activation, survival, proliferation, differentiation and T/B cell interaction. <em>In vivo</em>, CMTM6 deficiency leads to a significant decrease in the anti-tumor activity of immune checkpoint blockade (ICB) therapy and B cell-dependent CD40 agonists. Collectively, B-cell intrinsic CMTM6 maintains B cell CD40 levels and signaling to promote B cell function and anti-tumor immunity.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5926-5943"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940645","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":"Hepatokine FGL1 drives endothelial injury and atherogenesis via integrin β1-mediated endothelial–mesenchymal transition","authors":"Yixiu Zhao,&nbsp;Huan Chen,&nbsp;Liuqing Yin,&nbsp;Ruirui Meng,&nbsp;Jiangfei Zheng,&nbsp;Yue Zhang,&nbsp;Zhiqi Wang,&nbsp;Yi Chen,&nbsp;Rui Xu,&nbsp;Jing Liu,&nbsp;Yanxi Li,&nbsp;Na An,&nbsp;Houwei Li,&nbsp;Yan Zhang","doi":"10.1016/j.apsb.2026.06.005","DOIUrl":"10.1016/j.apsb.2026.06.005","url":null,"abstract":"<div><div>Atherosclerosis is driven by metabolic dysregulation and endothelial dysfunction; however, the precise molecular mechanisms underlying its pathogenesis remain incompletely elucidated. Fibrinogen-like protein 1 (FGL1) is a well-established hepatokine with critical roles in regulating tumorigenesis and metabolic dysfunction, while its involvement in atherogenesis remains unclear. Our clinical and preclinical studies revealed elevated plasma FGL1 levels in atherosclerotic patients and mice, correlating with arterial stenosis severity. Prolonged high-fat diet exposure specifically upregulated hepatic FGL1 expression. Hepatic FGL1 overexpression accelerated atherosclerosis, while liver-specific knockdown reduced plaque burden. Exogenous administration of FGL1 accelerated endothelial injury and atherosclerosis progression. Mechanistically, liver-derived FGL1 accumulates in vascular endothelium through fibrinogen C-terminal domain Trp225-mediated binding to integrin <em>β</em>1's vWFA domain. This interaction promotes the conformational change of integrin <em>β</em>1 and the formation of integrin <em>β</em>1/ILK1 complex, co-activating FAK/ERK and Smad signaling to drive transcriptional reprogramming of endothelial cells. Therapeutic interventions targeting FGL1–integrin <em>β</em>1 axis by integrin <em>β</em>1 blocking antibody, FGL1-neutralizing antibody, or RGD peptide effectively attenuated endothelial injury and atherogenic progression in murine models. These findings establish hepatic FGL1 as a novel endocrine regulator of vascular pathophysiology, highlighting the FGL1–integrin <em>β</em>1 axis as a promising therapeutic target for endothelial protection and atherosclerosis management.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5901-5925"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940646","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":"Artificial “zombie” cells: An emerging platform for targeted drug delivery and disease treatment","authors":"Yu Sun,&nbsp;Jie Feng,&nbsp;Ye Xing,&nbsp;Ping Sun,&nbsp;Minghui Liao,&nbsp;Xiaoyan Tan,&nbsp;Yi Wang","doi":"10.1016/j.apsb.2026.06.037","DOIUrl":"10.1016/j.apsb.2026.06.037","url":null,"abstract":"<div><div>Living cell therapy represents a promising strategy for targeted drug delivery and personalized medicine. However, its clinical translation is limited by complex isolation procedures, stringent storage conditions, and inherent risks of pathogenicity. Derived from this approach, cell membrane-coated carrier technology also faces challenges related to scalability and intricate multistep fabrication. To overcome these limitations, artificial “zombie” cells (AZCs) therapy has emerged as an innovative alternative. This therapy employs simple methods, such as cryogenic shock, intracellular hydrogelation, or cryo-siliconization, to inactivate cells. This process eliminates potential pathogenicity while preserving membrane integrity and drug-loading functionality. Based on the intact cellular structure or engineering approaches, these “zombie” cells gain drug-loading capacity, targeting ability, and therapeutic potential. Compared to traditional therapies, AZCs therapy requires simplified processing and offers enhanced stability and improved safety, demonstrating promising efficacy in treating various cancerous and inflammatory diseases. Current AZCs exhibit diverse types, heterogeneous preparation methods and varied therapeutic mechanisms, highlighting the lack of systematic consolidation in this field. Therefore, this review comprehensively analyzes their preparation technologies, functionalization strategies, mechanisms of action, and disease applications of AZCs, to evaluate current research progress and clinical potential, offering insights to advance preclinical-to-clinical translation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5650-5673"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148961101","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":"Cover Story","authors":"","doi":"10.1016/S2211-3835(26)00495-8","DOIUrl":"10.1016/S2211-3835(26)00495-8","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Page xvii"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148949546","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":"Tumor-responsive nanoparticles precisely overcome hypoxia-mediated STING dysfunction to unleash potent antitumor immunity","authors":"Linna Hai,&nbsp;Jian Wang,&nbsp;Dan Liu,&nbsp;Kaiqing Yun,&nbsp;Kongshuo Ma,&nbsp;Yuxuan Peng,&nbsp;Mengdi Xu,&nbsp;Xinbo Ma,&nbsp;Shan Gao,&nbsp;Qin Wang,&nbsp;Jiahui Zhou,&nbsp;Shuang Liang,&nbsp;Zhaohui Wang","doi":"10.1016/j.apsb.2026.06.043","DOIUrl":"10.1016/j.apsb.2026.06.043","url":null,"abstract":"<div><div>The Stimulator of Interferon Genes (STING) pathway plays a central role in anti-tumor immunity by mobilizing both the innate and adaptive immunity. However, hypoxia, a tumor hallmark was shown to severely constrain immune responses and lead to suboptimal therapeutic efficacy. Through bioinformatic analyses, we revealed that hypoxia directly repress STING-pathway-related genes. Furthermore, we developed tumor-targeted pH-responsive nanoparticles (SPF) to overcome hypoxia-induced STING dysfunction for amplifying immune responses. The nanoparticles (NPs) effectively accumulate and reoxygenate the hypoxic tumor, achieving a potent STING activation with enhanced secretion of type-I IFNs and other inflammatory cytokines. Moreover, SPF are capable of decreasing Tregs and polarizing M2 to M1 macrophages, thus creating an immune-promoting microenvironment to unleash cascade immune response. In colon cancer models, SPF NPs strongly inhibited tumor growth with 33% tumor-free over 50 days and long-term immune memory. Importantly, robust STING activation was achieved in human tumor samples with a substantial 782.3-fold of IFN-<em>β</em> and 1683.8-fold CXCL10 over control, highlighting the significance of hypoxia overcoming on STING activation in clinical settings. This study demonstrates a tumor-responsive nanomedicine with precise spatiotemporal control of hypoxia relief to overcome STING resistance, guiding the rational design and clinical translation of therapeutics for next-generation cancer immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6203-6220"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940083","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 the SETD2–FTO–KIT pathway as a pharmacological strategy for TKI-refractory GIST","authors":"Zhi Li,&nbsp;Junju He,&nbsp;Zhen Cao,&nbsp;Shishan Zhou,&nbsp;Yongwei Zhu,&nbsp;Yumei Duan,&nbsp;Anfeng Jiang,&nbsp;Yidi Guan,&nbsp;Jie Gao,&nbsp;Jian Tian,&nbsp;Liyu Liu,&nbsp;Zhuoxian Rong,&nbsp;Heli Liu,&nbsp;Xiaowei Liu,&nbsp;Hengyi Xiao,&nbsp;Yuezhen Deng,&nbsp;Bin Li,&nbsp;Lunquan Sun","doi":"10.1016/j.apsb.2026.07.016","DOIUrl":"10.1016/j.apsb.2026.07.016","url":null,"abstract":"<div><div>Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes in gastrointestinal stromal tumors (GIST), but acquired resistance remains a major clinical obstacle. The underlying mechanisms that sustain oncogenic KIT signaling in TKI-refractory GIST are not fully understood. Here, we identify a previously unrecognized epigenetic–epitranscriptomic regulatory axis involving SETD2, FTO, and KIT that promotes TKI resistance by stabilizing <em>KIT</em> mRNA. FTO, a key <em>N</em>⁶-methyladenosine (m⁶A) RNA demethylase, was found to be markedly overexpressed in high-risk and recurrent GIST samples and correlated with poor prognosis. Mechanistically, FTO enhances <em>KIT</em> mRNA stability by erasing m⁶A modification in its 3′ untranslated region (UTR), thereby preventing YTHDF2-mediated degradation and sustaining oncogenic KIT expression. Furthermore, the histone methyltransferase SETD2 activates <em>FTO</em> transcription <em>via</em> H3K36 trimethylation at the <em>FTO</em> promoter, establishing a self-reinforcing loop that maintains FTO overexpression. Functional experiments using <em>FTO</em> knockout and pharmacological inhibition (CS1 and entacapone) demonstrated that disrupting FTO activity suppresses tumor proliferation, reduces KIT expression, and restores sensitivity to imatinib both <em>in vitro</em> and <em>in vivo</em>. In KIT-Asp818Tyr/+ genetically engineered GIST mouse models, the combination of entacapone and imatinib led to significant tumor regression. Most importantly, preliminary clinical results from a Phase I trial (ClinicalTrials.gov: <span><span>NCT04006769</span><svg><path></path></svg></span>) showed that treatment with entacapone plus imatinib resulted in partial remission in two out of three evaluable TKI-refractory GIST patients, supporting the translational relevance of this strategy. Collectively, our findings establish the SETD2–FTO–KIT axis as a critical mechanism driving drug resistance in GIST and reveal m⁶A demethylation as a key regulator of <em>KIT</em> mRNA stability. Targeting FTO represents a promising and actionable therapeutic strategy to overcome TKI resistance and improve outcomes for patients with advanced GIST.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6045-6065"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940227","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":"Commentary beyond the ATP site: Cryo-EM views of allosteric PI3Kα inhibition","authors":"Benjamin G. Paetzel,&nbsp;John E. Burke","doi":"10.1016/j.apsb.2026.08.014","DOIUrl":"10.1016/j.apsb.2026.08.014","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6296-6298"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940586","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":"Author correction to “A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy” [Acta Pharm Sin B 13 (2023) 298–314]","authors":"Yongchao Chu,&nbsp;Yifan Luo,&nbsp;Boyu Su,&nbsp;Chao Li,&nbsp;Qin Guo,&nbsp;Yiwen Zhang,&nbsp;Peixin Liu,&nbsp;Hongyi Chen,&nbsp;Zhenhao Zhao,&nbsp;Zheng Zhou,&nbsp;Yu Wang,&nbsp;Chen Jiang,&nbsp;Tao Sun","doi":"10.1016/j.apsb.2026.06.039","DOIUrl":"10.1016/j.apsb.2026.06.039","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6301-6306"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940587","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}