Traditional drug discovery suffers from low efficiency and high attrition rates, largely due to the complexity and heterogeneity of human diseases. Omics technologies offer a systems-level perspective for uncovering disease mechanisms and identifying therapeutic targets, but present challenges such as high dimensionality, noise, and heterogeneity. Large language models (LLMs), originally developed for natural language processing, are emerging as powerful tools to address these issues by capturing complex patterns and inferring missing information from large, noisy datasets. We present a three-part framework: (1) Analyzing how LLM architectures and learning paradigms handle challenges specific to genomics, transcriptomics, and proteomics data; (2) Detailing LLM applications in key areas: uncovering disease mechanisms, identifying drug targets, predicting drug response, and simulating cellular behavior; (3) Discussing how insights from omics-integrated LLMs can inform the development of drugs targeting specific pathways, moving beyond single targets towards strategies grounded in underlying disease biology. This framework provides both conceptual insights and practical guidance for leveraging LLMs in omics-driven drug discovery and development.
{"title":"Omics-based large language models: A new engine for drug discovery innovation","authors":"Xia Sheng , Xiaoya Zhang , Yuxin Xing , Yuqi Shi , Chuanlong Zeng , Xiaochu Tong , Mingyue Zheng , Xutong Li","doi":"10.1016/j.apsb.2025.10.034","DOIUrl":"10.1016/j.apsb.2025.10.034","url":null,"abstract":"<div><div>Traditional drug discovery suffers from low efficiency and high attrition rates, largely due to the complexity and heterogeneity of human diseases. Omics technologies offer a systems-level perspective for uncovering disease mechanisms and identifying therapeutic targets, but present challenges such as high dimensionality, noise, and heterogeneity. Large language models (LLMs), originally developed for natural language processing, are emerging as powerful tools to address these issues by capturing complex patterns and inferring missing information from large, noisy datasets. We present a three-part framework: (1) Analyzing how LLM architectures and learning paradigms handle challenges specific to genomics, transcriptomics, and proteomics data; (2) Detailing LLM applications in key areas: uncovering disease mechanisms, identifying drug targets, predicting drug response, and simulating cellular behavior; (3) Discussing how insights from omics-integrated LLMs can inform the development of drugs targeting specific pathways, moving beyond single targets towards strategies grounded in underlying disease biology. This framework provides both conceptual insights and practical guidance for leveraging LLMs in omics-driven drug discovery and development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 122-136"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941478","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 : 2026-01-01Epub Date: 2025-11-24DOI: 10.1016/j.apsb.2025.11.026
Rui Li , Tian-Le Gao , Gang Ren , Lu-Lu Wang , Jian-Dong Jiang
Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs–neg-entropy–dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.
{"title":"Neg-entropy is the true drug target for chronic diseases","authors":"Rui Li , Tian-Le Gao , Gang Ren , Lu-Lu Wang , Jian-Dong Jiang","doi":"10.1016/j.apsb.2025.11.026","DOIUrl":"10.1016/j.apsb.2025.11.026","url":null,"abstract":"<div><div>Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs–neg-entropy–dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 231-238"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941389","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 : 2026-01-01Epub Date: 2025-10-28DOI: 10.1016/j.apsb.2025.10.031
Yu Zhu , Zhibi Zhang , Xueqin Dai , Wenjing Liu , Jian Sun , Jialing Liu , Yuxin Zhao , Wenlong Ren , Chenglong Pan , Zhongmei Zhou , Ying Yan , Longlong Zhang , Ceshi Chen
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from Munronia henryi, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts in vivo with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.
{"title":"DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer","authors":"Yu Zhu , Zhibi Zhang , Xueqin Dai , Wenjing Liu , Jian Sun , Jialing Liu , Yuxin Zhao , Wenlong Ren , Chenglong Pan , Zhongmei Zhou , Ying Yan , Longlong Zhang , Ceshi Chen","doi":"10.1016/j.apsb.2025.10.031","DOIUrl":"10.1016/j.apsb.2025.10.031","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from <em>Munronia henryi</em>, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts <em>in vivo</em> with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 287-304"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941393","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 : 2026-01-01Epub Date: 2025-10-13DOI: 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 : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.apsb.2025.11.030
Joshua Kramer , Eric Rohwer , Palaniappan Sethu , Min Xie , Timmy Lee , Victor Darley-Usmar , Jianhua Zhang
Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
{"title":"Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology","authors":"Joshua Kramer , Eric Rohwer , Palaniappan Sethu , Min Xie , Timmy Lee , Victor Darley-Usmar , Jianhua Zhang","doi":"10.1016/j.apsb.2025.11.030","DOIUrl":"10.1016/j.apsb.2025.11.030","url":null,"abstract":"<div><div>Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 1-12"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941473","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.2026.01.014
Tianjiao Hao, Bin Gao, Yuanyuan Zhou, Chang Liu, Chuanjiang Ran, Bi-Ing Chang, Wei You, Qiyue Wang, Jun Ye, Yan Shen
{"title":"A spatiotemporal selective bioinspired hybrid system engineered for preventing post-thrombolysis recurrence by inhibiting the ferroptosis pathway and reprogramming macrophages","authors":"Tianjiao Hao, Bin Gao, Yuanyuan Zhou, Chang Liu, Chuanjiang Ran, Bi-Ing Chang, Wei You, Qiyue Wang, Jun Ye, Yan Shen","doi":"10.1016/j.apsb.2026.01.014","DOIUrl":"https://doi.org/10.1016/j.apsb.2026.01.014","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381906","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}
Pub Date : 2026-01-01Epub Date: 2025-10-31DOI: 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 : 2026-01-01Epub Date: 2025-11-27DOI: 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 : 2026-01-01Epub Date: 2025-11-05DOI: 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 : 2026-01-01Epub Date: 2025-10-24DOI: 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}
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