Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.005
Xue Liu , Yalan Lu , Qichen Chen , Minjian Yang , Shize Li , Hanyu Sun , Xiangying Liu , Jingjie Yan , Liangning Li , Nan Xiang , Yan Lu , Qi Geng , Yiqiao Deng , Baolian Wang , Jing Jin , Hong Zhao , Xiandao Pan , Ahmed Al-Harrasi , Tingting Du , Wei Song , Xiaojian Wang
Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action. However, conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive. Fortunately, deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties. Herein, we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs. Through wet-lab validation, WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells. Furthermore, the R-(−)-WJ0909 (WJ0909B), demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids (PDOs). Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis. Moreover, WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models. This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.
{"title":"Deep learning-based discovery of tetrahydrocarbazoles as broad-spectrum antitumor agents and click-activated strategy for targeted cancer therapy","authors":"Xue Liu , Yalan Lu , Qichen Chen , Minjian Yang , Shize Li , Hanyu Sun , Xiangying Liu , Jingjie Yan , Liangning Li , Nan Xiang , Yan Lu , Qi Geng , Yiqiao Deng , Baolian Wang , Jing Jin , Hong Zhao , Xiandao Pan , Ahmed Al-Harrasi , Tingting Du , Wei Song , Xiaojian Wang","doi":"10.1016/j.apsb.2025.10.005","DOIUrl":"10.1016/j.apsb.2025.10.005","url":null,"abstract":"<div><div>Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action. However, conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive. Fortunately, deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties. Herein, we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs. Through wet-lab validation, WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells. Furthermore, the <em>R</em>-(−)-WJ0909 (WJ0909B), demonstrated optimal antitumor efficacy <em>in vitro</em> and <em>ex vivo</em> patient-derived organoids (PDOs). Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis. Moreover, WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models. This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 406-422"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941530","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.039
Xuecen Wang , Yuxuan Zhao , Xingli Yang , Tingyu Liu , Weilin Zhou , Shaoqing Niu , Meng Jin , Yong Chen , Ran-yi Liu , Yong Bao , Xin Yue
Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.
{"title":"Radiation-induced nuclear translocation of NPRL2 hijacks E3 ubiquitin ligases to enhance DNA repair via the AMPK/WDR24 axis, contributing to CRC radioresistance","authors":"Xuecen Wang , Yuxuan Zhao , Xingli Yang , Tingyu Liu , Weilin Zhou , Shaoqing Niu , Meng Jin , Yong Chen , Ran-yi Liu , Yong Bao , Xin Yue","doi":"10.1016/j.apsb.2025.10.039","DOIUrl":"10.1016/j.apsb.2025.10.039","url":null,"abstract":"<div><div>Radiotherapy resistance remains a major clinical challenge in colorectal cancer (CRC) treatment. Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity. We identify NPRL2 as the central mediator of this process. Following radiation, NPRL2 rapidly translocates to the nucleus, where it directly binds to the catalytic domains of key E3 ubiquitin ligases, including HERC2 and RNF8, and functionally inactivates them. This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins. Importantly, clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance. Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24, which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation. Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation, leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both <em>in vitro</em> and <em>in vivo</em> models. These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC, but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 252-269"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941391","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.025
Chen Shi , Hong Zhou , Liangru Zhu , Liyan Miao , Hong Yang , Kaichun Wu , Bikui Zhang , Jinhan He , Mengli Chen , Qian Cao , Jie Liang , Ren Mao , Xiao Chen , Rongsheng Zhao , Bo Zhang , Houwen Lin , Jingwen Wang , Xiaoyang Lu , Jun Xia , Xiaomei Yao , Yu Zhang
Therapeutic drug monitoring (TDM) has emerged as a valuable tool for optimizing the use of biologics in inflammatory bowel disease (IBD). However, variations in focus, methodology, and recommendations among relevant guidelines and consensuses have contributed to inconsistencies in their quality. This guideline synthesizes current evidence to standardize TDM of biologics in IBD, and improve patient outcomes. This multidisciplinary guideline was developed in collaboration with pharmacy, gastroenterology, and pharmacology associations in China. The guideline development group included 9 experts in clinical pharmacy, 4 experts in TDM, 8 gastroenterologists, and 2 methodologists. A comprehensive search was conducted across PubMed, Embase, Web of Science, the Cochrane Library databases, as well as key gastroenterology-relevant guideline websites. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was utilized, and this guideline was registered on the Guideline International Network website. Internal and external reviews were conducted. We proposed 5 clinical questions under two overarching themes. Based on the current evidence and the clinical opinions of the core working group members, the initial recommendations were made. Following comprehensive internal and external review processes, 14 recommendations (1 strong and 13 weak) were finalized for the clinical questions. To our knowledge, this is the first evidence-based clinical practice guideline on TDM in patients with IBD developed using the GRADE approach. It addresses five key questions: whether TDM leads to better therapeutic outcomes than conventional treatment, what indicators should be monitored, when TDM should be initiated, what the therapeutic drug trough concentration thresholds are, and which TDM method (proactive or reactive) can better improve therapeutic outcomes.
治疗性药物监测（TDM）已成为优化炎症性肠病（IBD）生物制剂使用的有价值的工具。然而，在相关的指导方针和共识中，焦点、方法和建议的变化导致了其质量的不一致。本指南综合了目前的证据，以规范IBD中生物制剂的TDM，并改善患者的预后。该多学科指南是与中国药学、胃肠病学和药理学协会合作制定的。指南制定小组包括9名临床药学专家、4名TDM专家、8名胃肠病学专家和2名方法学专家。在PubMed、Embase、Web of Science、Cochrane图书馆数据库以及关键的胃肠病学相关指南网站上进行了全面的搜索。采用推荐、评估、发展和评价分级（GRADE）方法，该指南已在指南国际网络网站上注册。进行了内部和外部审查。我们在两个总体主题下提出了5个临床问题。根据目前的证据和核心工作组成员的临床意见，提出了初步建议。经过全面的内部和外部审查过程，针对临床问题最终确定了14项建议（1项强建议和13项弱建议）。据我们所知，这是第一个使用GRADE方法制定的IBD患者TDM循证临床实践指南。它解决了五个关键问题：TDM是否比常规治疗带来更好的治疗结果，应该监测哪些指标，何时开始TDM，治疗药物谷浓度阈值是什么，以及哪种TDM方法（主动或被动）可以更好地改善治疗结果。
{"title":"Therapeutic drug monitoring of biologics in inflammatory bowel disease: An evidence-based multidisciplinary guideline","authors":"Chen Shi , Hong Zhou , Liangru Zhu , Liyan Miao , Hong Yang , Kaichun Wu , Bikui Zhang , Jinhan He , Mengli Chen , Qian Cao , Jie Liang , Ren Mao , Xiao Chen , Rongsheng Zhao , Bo Zhang , Houwen Lin , Jingwen Wang , Xiaoyang Lu , Jun Xia , Xiaomei Yao , Yu Zhang","doi":"10.1016/j.apsb.2025.11.025","DOIUrl":"10.1016/j.apsb.2025.11.025","url":null,"abstract":"<div><div>Therapeutic drug monitoring (TDM) has emerged as a valuable tool for optimizing the use of biologics in inflammatory bowel disease (IBD). However, variations in focus, methodology, and recommendations among relevant guidelines and consensuses have contributed to inconsistencies in their quality. This guideline synthesizes current evidence to standardize TDM of biologics in IBD, and improve patient outcomes. This multidisciplinary guideline was developed in collaboration with pharmacy, gastroenterology, and pharmacology associations in China. The guideline development group included 9 experts in clinical pharmacy, 4 experts in TDM, 8 gastroenterologists, and 2 methodologists. A comprehensive search was conducted across PubMed, Embase, Web of Science, the Cochrane Library databases, as well as key gastroenterology-relevant guideline websites. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was utilized, and this guideline was registered on the Guideline International Network website. Internal and external reviews were conducted. We proposed 5 clinical questions under two overarching themes. Based on the current evidence and the clinical opinions of the core working group members, the initial recommendations were made. Following comprehensive internal and external review processes, 14 recommendations (1 strong and 13 weak) were finalized for the clinical questions. To our knowledge, this is the first evidence-based clinical practice guideline on TDM in patients with IBD developed using the GRADE approach. It addresses five key questions: whether TDM leads to better therapeutic outcomes than conventional treatment, what indicators should be monitored, when TDM should be initiated, what the therapeutic drug trough concentration thresholds are, and which TDM method (proactive or reactive) can better improve therapeutic outcomes.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 616-641"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941462","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.002
Linlin Gong , Shasha Li , Jiahui Sun , Kunhong Liu , Simeng Wang , Meiju Ji , Peng Hou , Li Yan , Dan Yang , Dechun Liu
Proteolysis targeting chimeras (PROTACs) technology has been developed as an exquisite promising approach for targeted protein degradation by hijacking the cellular ubiquitin-proteasome system (UPS). However, traditional PROTACs often suffer from insufficient tumor accumulation, unfavorable membrane penetration, and always-on biological activity, limiting their antitumor performance. Herein, we report a novel pH-activatable engineered nanoparticle-based selective hexokinase 2 degrader (Nano-PROTACs) for cancer therapy. Nano-PROTACs were constructed by conjugating PEI-based PROTACs to amphiphilic nanoparticles via acid-detachable cis-aconitic anhydride (CAA) bonds. Then, Nano-PROTACs allowed PEI-based PROTACs release within the tumor acidic microenvironment, which bounded to HK-2 and recruited cereblon (CRBN) to provoke HK-2 ubiquitination for achieving HK-2 degradation via UPS. Interestingly, Nano-PROTACs specifically evoked GSDME-mediated pyroptosis to enhance cancer therapy. Thus, Nano-PROTACs effectively inhibited the growth of CT26 tumors and prevented tumor growth and lung metastasis in the orthotopic 4T1-luciferase tumor-bearing mouse model. Taken together, this study might offer a nanoparticle-based PROTACs platform for advancing selective protein of interest (POI) degradation in cancer therapy.
{"title":"pH-Activatable engineered nanoparticle-based selective hexokinase 2 degrader provokes GSDME-dependent pyroptosis for cancer therapy","authors":"Linlin Gong , Shasha Li , Jiahui Sun , Kunhong Liu , Simeng Wang , Meiju Ji , Peng Hou , Li Yan , Dan Yang , Dechun Liu","doi":"10.1016/j.apsb.2025.11.002","DOIUrl":"10.1016/j.apsb.2025.11.002","url":null,"abstract":"<div><div>Proteolysis targeting chimeras (PROTACs) technology has been developed as an exquisite promising approach for targeted protein degradation by hijacking the cellular ubiquitin-proteasome system (UPS). However, traditional PROTACs often suffer from insufficient tumor accumulation, unfavorable membrane penetration, and always-on biological activity, limiting their antitumor performance. Herein, we report a novel pH-activatable engineered nanoparticle-based selective hexokinase 2 degrader (Nano-PROTACs) for cancer therapy. Nano-PROTACs were constructed by conjugating PEI-based PROTACs to amphiphilic nanoparticles <em>via</em> acid-detachable <em>cis</em>-aconitic anhydride (CAA) bonds. Then, Nano-PROTACs allowed PEI-based PROTACs release within the tumor acidic microenvironment, which bounded to HK-2 and recruited cereblon (CRBN) to provoke HK-2 ubiquitination for achieving HK-2 degradation <em>via</em> UPS. Interestingly, Nano-PROTACs specifically evoked GSDME-mediated pyroptosis to enhance cancer therapy. Thus, Nano-PROTACs effectively inhibited the growth of CT26 tumors and prevented tumor growth and lung metastasis in the orthotopic 4T1-luciferase tumor-bearing mouse model. Taken together, this study might offer a nanoparticle-based PROTACs platform for advancing selective protein of interest (POI) degradation in cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 539-554"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941495","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.024
Hanxi Zhang , Jiazhen Lv , Wanyi Zhou , Jiangping Lei , Yu Yang , Jianqiao Kong , Chunhui Wu , Chuan Zheng , Fengming You , Yiyao Liu , Hong Yang
Therapeutic tumor vaccines have emerged as promising weapons for inducing robust and durable antitumor immune responses, demonstrating substantial potential for cancer treatment. However, clinical efficacy is significantly hindered by tumor immunogenicity scarcity, antigen presentation deficiency, and immunosuppressive tumor microenvironment. To surmount these obstacles, we proposed an injectable photoimmunological hydrogel vaccine (CRPO/G@ALG) to improve immunotherapy outcomes through the dual mechanism of immunogenic cell death (ICD) induction and dendritic cell (DC) recruitment. The model antigen ovalbumin (OVA) and toll-like receptor 7/8 agonist resiquimod (R848) were incorporated into photothermal copper sulfide nanoparticles (CuS) to construct the nanovaccine CRPO, which was subsequently encapsulated with the granulocyte-macrophage colony-stimulating factor (GM-CSF) in sodium alginate (ALG) to form the hydrogel vaccine CRPO/G@ALG. Following peritumoral administration, CRPO/G@ALG undergoes gelation in response to physiological calcium ions, facilitating the localized retention and controlled release of payloads. Near-infrared (NIR) irradiation triggers ICD in tumor cells, generating an in situ antigen reservoir enriched with tumor-associated antigens (TAAs) to bolster tumor immunogenicity. Concurrently, GM-CSF attracts DCs to infiltrate tumor tissues, while R848 promotes DC maturation and antigen cross-presentation. These synergistic effects prolong the duration of immune stimulation and expand both the breadth and depth of antitumor immunity. In 4T1 tumor-bearing mice, CRPO/G@ALG effectively suppressed primary and distant tumor growth and markedly reduced lung metastasis. Collectively, our findings illustrate the transformative potential of integrating ICD induction, DC recruitment, and hydrogel delivery systems, offering new avenues to advance therapeutic tumor vaccine applications.
{"title":"Photoimmunological hydrogel vaccine creates a supportive immune niche to promote antigen cross-presentation cascade and cancer-immunity cycle progression","authors":"Hanxi Zhang , Jiazhen Lv , Wanyi Zhou , Jiangping Lei , Yu Yang , Jianqiao Kong , Chunhui Wu , Chuan Zheng , Fengming You , Yiyao Liu , Hong Yang","doi":"10.1016/j.apsb.2025.10.024","DOIUrl":"10.1016/j.apsb.2025.10.024","url":null,"abstract":"<div><div>Therapeutic tumor vaccines have emerged as promising weapons for inducing robust and durable antitumor immune responses, demonstrating substantial potential for cancer treatment. However, clinical efficacy is significantly hindered by tumor immunogenicity scarcity, antigen presentation deficiency, and immunosuppressive tumor microenvironment. To surmount these obstacles, we proposed an injectable photoimmunological hydrogel vaccine (CRPO/G@ALG) to improve immunotherapy outcomes through the dual mechanism of immunogenic cell death (ICD) induction and dendritic cell (DC) recruitment. The model antigen ovalbumin (OVA) and toll-like receptor 7/8 agonist resiquimod (R848) were incorporated into photothermal copper sulfide nanoparticles (CuS) to construct the nanovaccine CRPO, which was subsequently encapsulated with the granulocyte-macrophage colony-stimulating factor (GM-CSF) in sodium alginate (ALG) to form the hydrogel vaccine CRPO/G@ALG. Following peritumoral administration, CRPO/G@ALG undergoes gelation in response to physiological calcium ions, facilitating the localized retention and controlled release of payloads. Near-infrared (NIR) irradiation triggers ICD in tumor cells, generating an <em>in situ</em> antigen reservoir enriched with tumor-associated antigens (TAAs) to bolster tumor immunogenicity. Concurrently, GM-CSF attracts DCs to infiltrate tumor tissues, while R848 promotes DC maturation and antigen cross-presentation. These synergistic effects prolong the duration of immune stimulation and expand both the breadth and depth of antitumor immunity. In 4T1 tumor-bearing mice, CRPO/G@ALG effectively suppressed primary and distant tumor growth and markedly reduced lung metastasis. Collectively, our findings illustrate the transformative potential of integrating ICD induction, DC recruitment, and hydrogel delivery systems, offering new avenues to advance therapeutic tumor vaccine applications.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 555-573"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941499","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.043
Chunsen Yuan , Taotao Jin , Hangke Lei , Juanjuan Liu , Wendan Pu , Yang Zhang , Chenwen Li , Dingde Huang , Jianxiang Zhang , Jiawei Guo
{"title":"Author correction to “Self-illuminating liposome-derived in situ triggerable photodynamic therapy combining radionuclide therapy for synergistic treatment of lung cancer” [Acta Pharm Sin B 15 (2025) 4973–4994]","authors":"Chunsen Yuan , Taotao Jin , Hangke Lei , Juanjuan Liu , Wendan Pu , Yang Zhang , Chenwen Li , Dingde Huang , Jianxiang Zhang , Jiawei Guo","doi":"10.1016/j.apsb.2025.10.043","DOIUrl":"10.1016/j.apsb.2025.10.043","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 660-663"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941471","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.047
Baohu Li , Hui Xu , Xiaoyu Shi , Chunhua Ma , Jinfei Yang , Peng Zhan
{"title":"Clinical insight-driven novel drug development: Multidisciplinary integration and transformative opportunities","authors":"Baohu Li , Hui Xu , Xiaoyu Shi , Chunhua Ma , Jinfei Yang , Peng Zhan","doi":"10.1016/j.apsb.2025.10.047","DOIUrl":"10.1016/j.apsb.2025.10.047","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 651-655"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941472","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.09.037
Yaqi Yuan , Peng Jiang , Chuan Xiao , Jiapeng Lei , Bo Cheng , Hankun Hu , Wei Li
Psoriasis is a prevalent chronic inflammatory skin disorder, characterized by epidermal thickening and an inflammatory hypoxic microenvironment, which significantly hinder drug penetration through the thickened skin and limit the efficacy of photodynamic therapy (PDT). Here, we introduce a dual-section microneedle (MN) patch (termed S-PTP MN patch) to enhance the therapeutic efficacy of psoriasis treatment. The needle section contains PTP nanoparticles (NPs) loaded with triamcinolone acetonide (TA) and coated with a reactive oxygen species (ROS)-responsive layer, while the base section of the patch encapsulates sodium percarbonate (SPC) particles that serve as oxygen generators to facilitate deep penetration of the PTP NPs into inflammatory sites and improve PDT efficacy. Moreover, the PTP NPs enable sustained release of TA drug over 6 days, demonstrating potent anti-inflammatory activity. In an imiquimod-induced psoriatic mouse model, a single application of the S-PTP MN patch demonstrated superior therapeutic efficacy compared to the conventional topical TA cream, with significantly alleviated clinical symptoms, reduced epidermal thickness, and lowered inflammatory cytokine levels, highlighting the potential of the S-PTP MN patch as a clinically translatable strategy for effective psoriasis therapy.
{"title":"Oxygen-boosted dual-section microneedle patch for enhanced drug penetration and improved photodynamic and anti-inflammatory therapy in psoriasis","authors":"Yaqi Yuan , Peng Jiang , Chuan Xiao , Jiapeng Lei , Bo Cheng , Hankun Hu , Wei Li","doi":"10.1016/j.apsb.2025.09.037","DOIUrl":"10.1016/j.apsb.2025.09.037","url":null,"abstract":"<div><div>Psoriasis is a prevalent chronic inflammatory skin disorder, characterized by epidermal thickening and an inflammatory hypoxic microenvironment, which significantly hinder drug penetration through the thickened skin and limit the efficacy of photodynamic therapy (PDT). Here, we introduce a dual-section microneedle (MN) patch (termed S-PTP MN patch) to enhance the therapeutic efficacy of psoriasis treatment. The needle section contains PTP nanoparticles (NPs) loaded with triamcinolone acetonide (TA) and coated with a reactive oxygen species (ROS)-responsive layer, while the base section of the patch encapsulates sodium percarbonate (SPC) particles that serve as oxygen generators to facilitate deep penetration of the PTP NPs into inflammatory sites and improve PDT efficacy. Moreover, the PTP NPs enable sustained release of TA drug over 6 days, demonstrating potent anti-inflammatory activity. In an imiquimod-induced psoriatic mouse model, a single application of the S-PTP MN patch demonstrated superior therapeutic efficacy compared to the conventional topical TA cream, with significantly alleviated clinical symptoms, reduced epidermal thickness, and lowered inflammatory cytokine levels, highlighting the potential of the S-PTP MN patch as a clinically translatable strategy for effective psoriasis therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 458-469"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941493","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.09.026
Hengyue Shan , Yuzheng Zhou , Ying Qin , Taijie Guo , Xiao Zhang , Huaijiang Xiang , Qinyang He , Chen Shi , Dekang Li , Jingli Liu , Chunting Qi , Shi Chen , Jiajia Dong , Gang Xu , Ying Li , Zheng Zhang , Li Tan
SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy in vivo has yet to be explored. Here, we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. Our lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development.
{"title":"Discovery of SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model","authors":"Hengyue Shan , Yuzheng Zhou , Ying Qin , Taijie Guo , Xiao Zhang , Huaijiang Xiang , Qinyang He , Chen Shi , Dekang Li , Jingli Liu , Chunting Qi , Shi Chen , Jiajia Dong , Gang Xu , Ying Li , Zheng Zhang , Li Tan","doi":"10.1016/j.apsb.2025.09.026","DOIUrl":"10.1016/j.apsb.2025.09.026","url":null,"abstract":"<div><div>SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy <em>in vivo</em> has yet to be explored. Here, we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. Our lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 387-405"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941528","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.032
Anqi Lin , Zhirou Zhang , Aimin Jiang , Kexin Li , Ying Shi , Hong Yang , Jian Zhang , Rongrong Liu , Yaxuan Wang , Antonino Glaviano , Quan Cheng , Bufu Tang , Zhengang Qiu , Peng Luo
With the rapid advancements in computer technology and bioinformatics, the prediction of protein–ligand-binding sites has become a central component of modern drug discovery and development. Traditional experimental methods are often constrained by long experimental cycles and high costs; therefore, the development of accurate and efficient computational methods is of paramount significance for conserving time and cost. This review comprehensively summarizes the methodological advancements and current applications in the field of screening for druggable protein target sites, systematically comparing the fundamental principles, advantages, and disadvantages of four main categories of methods: structure- and sequence-based methods, machine learning-based methods, binding site feature analysis methods, and druggability assessment methods. Subsequently, by integrating classic case studies, this paper elaborately discusses the technical support and theoretical guidance afforded by the screening of protein druggable target sites for drug discovery and drug repositioning. Finally, this paper thoroughly explores the current challenges inherent in the field of protein–ligand binding site prediction, with a particular focus on future technological trends, systematically elucidating the developmental prospects and potential applications of these predictive methods.
{"title":"Computational approaches to druggable site identification: Current status and future perspective","authors":"Anqi Lin , Zhirou Zhang , Aimin Jiang , Kexin Li , Ying Shi , Hong Yang , Jian Zhang , Rongrong Liu , Yaxuan Wang , Antonino Glaviano , Quan Cheng , Bufu Tang , Zhengang Qiu , Peng Luo","doi":"10.1016/j.apsb.2025.10.032","DOIUrl":"10.1016/j.apsb.2025.10.032","url":null,"abstract":"<div><div>With the rapid advancements in computer technology and bioinformatics, the prediction of protein–ligand-binding sites has become a central component of modern drug discovery and development. Traditional experimental methods are often constrained by long experimental cycles and high costs; therefore, the development of accurate and efficient computational methods is of paramount significance for conserving time and cost. This review comprehensively summarizes the methodological advancements and current applications in the field of screening for druggable protein target sites, systematically comparing the fundamental principles, advantages, and disadvantages of four main categories of methods: structure- and sequence-based methods, machine learning-based methods, binding site feature analysis methods, and druggability assessment methods. Subsequently, by integrating classic case studies, this paper elaborately discusses the technical support and theoretical guidance afforded by the screening of protein druggable target sites for drug discovery and drug repositioning. Finally, this paper thoroughly explores the current challenges inherent in the field of protein–ligand binding site prediction, with a particular focus on future technological trends, systematically elucidating the developmental prospects and potential applications of these predictive methods.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 62-92"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941476","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}
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