Pub Date : 2026-02-01Epub Date: 2025-12-03DOI: 10.1016/j.apsb.2025.12.002
Xia Zhao , Fan Chen , Li Xiong , Xiaoxia Xu , Ziyao Meng , Yu Deng , Qi Ai , Luyao Li , Qin Yu , Linjie Chen , Ruya Wang , Yiyu Ren , Wenhua Zheng , Jurui Wei , Houming Yu , Guang Liang
Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. Emerging evidence suggests that deubiquitinating enzymes (DUBs), which regulate protein homeostasis through the cleavage of ubiquitin chains, play critical roles in PD pathogenesis. In this study, we discovered that a DUB, ovarian tumor deubiquitinase 6A (OTUD6A), was significantly upregulated in both PD patients and PD mouse models. Notably, OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models. Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays, we identified that actin gamma 1 (ACTG1) serves as a key substrate of OTUD6A. Mechanistically, OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains, thereby enhancing ACTG1 protein stability in neuronal cells. The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation, leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis. Collectively, our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1, which in turn activates a p53-dependent apoptotic pathway. These findings identify OTUD6A as a potential therapeutic target for PD intervention.
{"title":"OTUD6A drives dopaminergic neuronal degeneration of Parkinson's disease through deubiquitinating ACTG1 in neuronal cells","authors":"Xia Zhao , Fan Chen , Li Xiong , Xiaoxia Xu , Ziyao Meng , Yu Deng , Qi Ai , Luyao Li , Qin Yu , Linjie Chen , Ruya Wang , Yiyu Ren , Wenhua Zheng , Jurui Wei , Houming Yu , Guang Liang","doi":"10.1016/j.apsb.2025.12.002","DOIUrl":"10.1016/j.apsb.2025.12.002","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. Emerging evidence suggests that deubiquitinating enzymes (DUBs), which regulate protein homeostasis through the cleavage of ubiquitin chains, play critical roles in PD pathogenesis. In this study, we discovered that a DUB, ovarian tumor deubiquitinase 6A (OTUD6A), was significantly upregulated in both PD patients and PD mouse models. Notably, OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models. Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays, we identified that actin gamma 1 (ACTG1) serves as a key substrate of OTUD6A. Mechanistically, OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains, thereby enhancing ACTG1 protein stability in neuronal cells. The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation, leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis. Collectively, our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1, which in turn activates a p53-dependent apoptotic pathway. These findings identify OTUD6A as a potential therapeutic target for PD intervention.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 820-835"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177277","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 : 2026-02-01Epub Date: 2025-12-24DOI: 10.1016/j.apsb.2025.12.034
Jialing Cheng , Zhiyang Chen , Demin Lin , Yanfang Yang , Yanjing Bai , Lingshuang Wang , Jie Li , Yuchen Wang , Hongliang Wang , Youbai Chen , Jun Ye , Yuling Liu
{"title":"Author correction to “A high clinically translatable strategy to anti-aging using hyaluronic acid and silk fibroin co-crosslinked hydrogels as dermal regenerative fillers” [Acta Pharmaceutica Sinica B 15 (2025) 3767–3787]","authors":"Jialing Cheng , Zhiyang Chen , Demin Lin , Yanfang Yang , Yanjing Bai , Lingshuang Wang , Jie Li , Yuchen Wang , Hongliang Wang , Youbai Chen , Jun Ye , Yuling Liu","doi":"10.1016/j.apsb.2025.12.034","DOIUrl":"10.1016/j.apsb.2025.12.034","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 1170-1172"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177191","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 : 2026-02-01Epub Date: 2025-12-04DOI: 10.1016/j.apsb.2025.12.005
Jiali Zhang , Xiangyu Wang , Xingang Liu , Jincan Li , Kening Qiao , Jinglei Sun , Jiabao Zuo , Weidong Zhao , Tenghui He , Xuedong Li , Zhengkun Guan , Yang Zhang , Yanfang Xu , Qingzhong Jia
Oxaliplatin, a chemotherapeutic agent commonly used in colorectal cancer treatment, frequently induces chemotherapy-induced peripheral neuropathy (CIPN), with mechanical allodynia as a dose-limiting neurological complication. However, the precise pathophysiological mechanism underlying this sensory dysfunction remains inadequately elucidated. This study identifies Kv4.3 channel dysfunction in C-low threshold mechanoreceptors (C-LTMRs), a subset of tyrosine hydroxylase–positive (TH+) sensory neurons in the dorsal root ganglia (DRG), as the critical driver of oxaliplatin-induced mechanical allodynia. Using electrophysiological, pharmacological, and genetic approaches in mouse models, we have demonstrated that oxaliplatin selectively alters the firing pattern of C-LTMRs and enhances their excitability, particularly in response to low-intensity stimuli. This effect is mediated by Kv4.3 channel dysfunction within C-LTMRs, which underlies the pathological conversion of innocuous touch to pain. Critically, pharmacological inhibition or neuron-specific knockdown of Kv4.3 channels exacerbated mechanical allodynia, while Kv4.3 channel activation reversed neuronal hyperexcitability and alleviated oxaliplatin-induced mechanical allodynia. Thus, Kv4.3 dysfunction constitutes a core pathogenic mechanism of oxaliplatin-induced mechanical allodynia. Targeted enhancement of the Kv4.3 channel activity in C-LTMRs represents a promising precision analgesic strategy for this condition.
{"title":"The Kv4.3 channel on c-low threshold mechanoreceptors in DRG is a key mediator transforming tactile stimuli into nociceptive signals in chemotherapy-induced neuropathy","authors":"Jiali Zhang , Xiangyu Wang , Xingang Liu , Jincan Li , Kening Qiao , Jinglei Sun , Jiabao Zuo , Weidong Zhao , Tenghui He , Xuedong Li , Zhengkun Guan , Yang Zhang , Yanfang Xu , Qingzhong Jia","doi":"10.1016/j.apsb.2025.12.005","DOIUrl":"10.1016/j.apsb.2025.12.005","url":null,"abstract":"<div><div>Oxaliplatin, a chemotherapeutic agent commonly used in colorectal cancer treatment, frequently induces chemotherapy-induced peripheral neuropathy (CIPN), with mechanical allodynia as a dose-limiting neurological complication. However, the precise pathophysiological mechanism underlying this sensory dysfunction remains inadequately elucidated. This study identifies Kv4.3 channel dysfunction in C-low threshold mechanoreceptors (C-LTMRs), a subset of tyrosine hydroxylase–positive (TH<sup>+</sup>) sensory neurons in the dorsal root ganglia (DRG), as the critical driver of oxaliplatin-induced mechanical allodynia. Using electrophysiological, pharmacological, and genetic approaches in mouse models, we have demonstrated that oxaliplatin selectively alters the firing pattern of C-LTMRs and enhances their excitability, particularly in response to low-intensity stimuli. This effect is mediated by Kv4.3 channel dysfunction within C-LTMRs, which underlies the pathological conversion of innocuous touch to pain. Critically, pharmacological inhibition or neuron-specific knockdown of Kv4.3 channels exacerbated mechanical allodynia, while Kv4.3 channel activation reversed neuronal hyperexcitability and alleviated oxaliplatin-induced mechanical allodynia. Thus, Kv4.3 dysfunction constitutes a core pathogenic mechanism of oxaliplatin-induced mechanical allodynia. Targeted enhancement of the Kv4.3 channel activity in C-LTMRs represents a promising precision analgesic strategy for this condition.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 854-878"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177283","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 : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.apsb.2025.10.008
Chunmao Yuan , Zhao Liu , Lei Huang , Chunxiang Mei , Yanrong Zeng , Yanmei Li , Yang Chen , Hongji Wang , Lan Yang , Xiaojiang Hao , Shuzhong He
Hyperimonates A (1) and B (2), two minor polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented hexahydro-1H-cyclopenta[c]furan-1-one and 2-oxabicyclo[2.2.1]heptane ring system were isolated from Hypericum monogynum. To obtain adequate materials for biological research, the asymmetric total syntheses of 1 and 2 were completed from commercially available geraniol via a bioinspired strategy that features an Au(I)-catalyzed carbometallic cascade cyclization and a Mn(III)/Cu(II) mediated oxidative radical cyclization as vital steps. Biological study implied that compound 1 showed excellent lipid-lowering activity in vitro via inhibiting two signaling pathways, Notch and PPAR, further verified by non-alcoholic fatty liver disease (NAFLD) zebrafish model. These findings provide a new structural template for the treatment of NAFLD and asymmetric synthetic approaches could also facilitate further evaluation for drug development.
{"title":"Hyperimonates A and B, a pair of unprecedented polyprenylated acylphloroglucinols from Hypericum monogynum: Structural elucidation, total synthesis, and lipid-lowering activity","authors":"Chunmao Yuan , Zhao Liu , Lei Huang , Chunxiang Mei , Yanrong Zeng , Yanmei Li , Yang Chen , Hongji Wang , Lan Yang , Xiaojiang Hao , Shuzhong He","doi":"10.1016/j.apsb.2025.10.008","DOIUrl":"10.1016/j.apsb.2025.10.008","url":null,"abstract":"<div><div>Hyperimonates A (<strong>1</strong>) and B (<strong>2</strong>), two minor polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented hexahydro-1<em>H</em>-cyclopenta[<em>c</em>]furan-1-one and 2-oxabicyclo[2.2.1]heptane ring system were isolated from <em>Hypericum monogynum</em>. To obtain adequate materials for biological research, the asymmetric total syntheses of <strong>1</strong> and <strong>2</strong> were completed from commercially available geraniol <em>via</em> a bioinspired strategy that features an Au(I)-catalyzed carbometallic cascade cyclization and a Mn(III)/Cu(II) mediated oxidative radical cyclization as vital steps. Biological study implied that compound <strong>1</strong> showed excellent lipid-lowering activity <em>in vitro via</em> inhibiting two signaling pathways, Notch and PPAR, further verified by non-alcoholic fatty liver disease (NAFLD) zebrafish model. These findings provide a new structural template for the treatment of NAFLD and asymmetric synthetic approaches could also facilitate further evaluation for drug development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 1009-1021"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177200","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 : 2026-02-01Epub Date: 2025-12-02DOI: 10.1016/j.apsb.2025.11.033
Yingjun Li , Jianfang Zhang , Fengming He , Cuiting Cao , Yangqing Zhan , Nanshan Zhong , Zifeng Yang
The rapid evolution of influenza viruses, driven by high mutation rates and cross-species transmission, underscores the importance of discovering antivirals with novel mechanisms of action and distinct resistance profiles. The influenza virus RNA polymerase, a highly conserved heterotrimeric complex, comprises polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses, or polymerase 3 protein (P3) in influenza C and D viruses. This complex is essential for viral genome replication and transcription, rendering it a critical target for antiviral intervention. Over the past two decades, research on influenza polymerase (FluPol) has advanced from fundamental studies to drug development and clinical application. By 2025, six FluPol-targeting drugs have received regulatory approval: the PA inhibitors baloxavir marboxil, suraxavir marboxil, seloxavir marboxil, and pixavir marboxil; the PB1 inhibitor favipiravir; and the PB2 inhibitor onradivir, with several additional candidates progressing to clinical research. This review summarizes the structure and function of influenza polymerase and the mechanisms of action of different inhibitors, highlighting the discovery and clinical effectiveness of the newly approved FluPol-targeting drugs. It addresses the potential of FluPol inhibitors against highly pathogenic avian influenza and the challenges posed by resistance mutations.
{"title":"Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics","authors":"Yingjun Li , Jianfang Zhang , Fengming He , Cuiting Cao , Yangqing Zhan , Nanshan Zhong , Zifeng Yang","doi":"10.1016/j.apsb.2025.11.033","DOIUrl":"10.1016/j.apsb.2025.11.033","url":null,"abstract":"<div><div>The rapid evolution of influenza viruses, driven by high mutation rates and cross-species transmission, underscores the importance of discovering antivirals with novel mechanisms of action and distinct resistance profiles. The influenza virus RNA polymerase, a highly conserved heterotrimeric complex, comprises polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses, or polymerase 3 protein (P3) in influenza C and D viruses. This complex is essential for viral genome replication and transcription, rendering it a critical target for antiviral intervention. Over the past two decades, research on influenza polymerase (FluPol) has advanced from fundamental studies to drug development and clinical application. By 2025, six FluPol-targeting drugs have received regulatory approval: the PA inhibitors baloxavir marboxil, suraxavir marboxil, seloxavir marboxil, and pixavir marboxil; the PB1 inhibitor favipiravir; and the PB2 inhibitor onradivir, with several additional candidates progressing to clinical research. This review summarizes the structure and function of influenza polymerase and the mechanisms of action of different inhibitors, highlighting the discovery and clinical effectiveness of the newly approved FluPol-targeting drugs. It addresses the potential of FluPol inhibitors against highly pathogenic avian influenza and the challenges posed by resistance mutations.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 728-745"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177468","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 : 2026-02-01Epub Date: 2025-12-04DOI: 10.1016/j.apsb.2025.12.004
Peng Jin , Minru Liao , Huidi Liu , Kun Huang , Leilei Fu , Xin Jin
Protein kinases, as one of the most important human enzymes, are signaling molecules that regulate almost all cell activities, including growth, cell division and metabolism. Dysfunction of these cellular pathways can lead to a variety of human diseases. Accumulating evidence on the down-regulation of key protein kinases in diseases has made a big progress. The down-regulation is related to cancer, heart disease, neurodegenerative diseases and other diseases. Thus, in this review, we defined the classifications of protein kinases and demonstrated the mechanisms of protein kinase activators in the treatment of human diseases, summarized the research progress of protein kinase activators, and further discussed the development progress of protein kinase activators in clinical stage. Accordingly, activation of protein kinases has become a crucial target for drug development. With the in-depth understanding of protein kinase functions and regulation mechanisms, the development of new protein kinase activators may continue to be a rapidly growing field, which will help to develop more accurate and effective targeted therapeutic strategies in the near future.
{"title":"Activating protein kinases to treat diseases: Current understanding and future challenges","authors":"Peng Jin , Minru Liao , Huidi Liu , Kun Huang , Leilei Fu , Xin Jin","doi":"10.1016/j.apsb.2025.12.004","DOIUrl":"10.1016/j.apsb.2025.12.004","url":null,"abstract":"<div><div>Protein kinases, as one of the most important human enzymes, are signaling molecules that regulate almost all cell activities, including growth, cell division and metabolism. Dysfunction of these cellular pathways can lead to a variety of human diseases. Accumulating evidence on the down-regulation of key protein kinases in diseases has made a big progress. The down-regulation is related to cancer, heart disease, neurodegenerative diseases and other diseases. Thus, in this review, we defined the classifications of protein kinases and demonstrated the mechanisms of protein kinase activators in the treatment of human diseases, summarized the research progress of protein kinase activators, and further discussed the development progress of protein kinase activators in clinical stage. Accordingly, activation of protein kinases has become a crucial target for drug development. With the in-depth understanding of protein kinase functions and regulation mechanisms, the development of new protein kinase activators may continue to be a rapidly growing field, which will help to develop more accurate and effective targeted therapeutic strategies in the near future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 746-769"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177460","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}
Artificial intelligence (AI) is a transformative technique for drug development, and it has been widely applied in pharmaceutical industry and academia. Pulmonary drug delivery systems (PDDS) are preferred for treating respiratory diseases due to their ability to provide localized and rapid action with fewer side effects. The integration of AI and Machine Learning (ML) has significantly accelerated the development of PDDS by enhancing both respiratory disease detection, and different stages during PDDS development. This paper provides an overview of the present landscape by literature analysis of the key areas of research. This review first introduces the fundamental principles of AI/ML and how they are applied in respiratory disease detection and diagnostics, highlighting FDA-approved software used in this field. Furthermore, we examine the role of AI in different stages during the development of PDDS, from identifying novel drug candidates to optimizing formulations and drug delivery mechanisms. The review also discusses regulatory and ethical considerations, along with existing challenges during AI-driven PDDS development. By addressing these key aspects, we provide insights into the revolutionary potential of AI/ML in advancing pulmonary drug delivery and improving therapeutic outcomes.
{"title":"Applications of AI/ML in accelerating the development of pulmonary drug delivery system","authors":"Junhuang Jiang , Ziling Zhou , Tingting Peng , Zhengwei Huang , Xin Pan , Chuanbin Wu","doi":"10.1016/j.apsb.2025.11.028","DOIUrl":"10.1016/j.apsb.2025.11.028","url":null,"abstract":"<div><div>Artificial intelligence (AI) is a transformative technique for drug development, and it has been widely applied in pharmaceutical industry and academia. Pulmonary drug delivery systems (PDDS) are preferred for treating respiratory diseases due to their ability to provide localized and rapid action with fewer side effects. The integration of AI and Machine Learning (ML) has significantly accelerated the development of PDDS by enhancing both respiratory disease detection, and different stages during PDDS development. This paper provides an overview of the present landscape by literature analysis of the key areas of research. This review first introduces the fundamental principles of AI/ML and how they are applied in respiratory disease detection and diagnostics, highlighting FDA-approved software used in this field. Furthermore, we examine the role of AI in different stages during the development of PDDS, from identifying novel drug candidates to optimizing formulations and drug delivery mechanisms. The review also discusses regulatory and ethical considerations, along with existing challenges during AI-driven PDDS development. By addressing these key aspects, we provide insights into the revolutionary potential of AI/ML in advancing pulmonary drug delivery and improving therapeutic outcomes.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 686-708"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177487","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 : 2026-02-01Epub Date: 2025-11-12DOI: 10.1016/j.apsb.2025.11.008
Zhirui Liu , Lunzhi Yuan , Pengyun Li , Fei Xie , Ming Zhou , Lianqi Liu , Ting Wei , Yi Guan , Ningshao Xia , Zhibing Zheng , Tong Cheng , Dian Xiao , Xinbo Zhou , Song Li
Despite remarkable achievements in antibody‒drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.
{"title":"Antibody‒drug conjugates with DHODH inhibitor as novel payload class for cancer and SARS-CoV-2 infection therapies","authors":"Zhirui Liu , Lunzhi Yuan , Pengyun Li , Fei Xie , Ming Zhou , Lianqi Liu , Ting Wei , Yi Guan , Ningshao Xia , Zhibing Zheng , Tong Cheng , Dian Xiao , Xinbo Zhou , Song Li","doi":"10.1016/j.apsb.2025.11.008","DOIUrl":"10.1016/j.apsb.2025.11.008","url":null,"abstract":"<div><div>Despite remarkable achievements in antibody‒drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC <strong>TH-C8H</strong> exhibited significant efficacy against gastric cancer <em>in vivo</em> as monotherapy and enhanced efficacy when combined with the ferroptosis inducer <strong>RSL3</strong>. The antiviral ADC <strong>HG-C3</strong> showed broad-spectrum anti-SARS-CoV-2 activity <em>in vitro</em> and <em>in vivo</em>. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 1046-1058"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177512","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 : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.apsb.2025.11.014
Yuanyuan Yu , Na An , Yi Chen , Ming Tong , Shuyu Liu , Yanrong Li , Hongbo Dong , Yanxi Li , Min Feng , Linhe Liu , Shifeng Cao , Huan Chen , Yixiu Zhao , Zhimin Du , Xin Zhao , Baofeng Yang , Yan Zhang
Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived β-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.
{"title":"Cold exposure-induced β-hydroxybutyrate promotes brown fat mitochondrial lipid droplet contact to ameliorate fatty dysfunction and hepatic steatosis","authors":"Yuanyuan Yu , Na An , Yi Chen , Ming Tong , Shuyu Liu , Yanrong Li , Hongbo Dong , Yanxi Li , Min Feng , Linhe Liu , Shifeng Cao , Huan Chen , Yixiu Zhao , Zhimin Du , Xin Zhao , Baofeng Yang , Yan Zhang","doi":"10.1016/j.apsb.2025.11.014","DOIUrl":"10.1016/j.apsb.2025.11.014","url":null,"abstract":"<div><div>Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived <em>β</em>-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 2","pages":"Pages 930-947"},"PeriodicalIF":14.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177221","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 : 2026-02-01Epub Date: 2025-07-25DOI: 10.1016/j.apsb.2025.07.031
Taoling Zeng , Tingting Jiang , Baoding Zhang , Ting Zhang , Wanjun Dai , Xun Yin , Yunzhan Li , Zhuoran Yu , Caiming Wu , Yaying Wu , Ximin Chi , Xianming Deng , Hong-Rui Wang
K-RAS mutations represent a most prevalent oncogenic alteration in human cancers. Despite tremendous efforts, it remains a big challenge to develop strategies that specifically target the oncogenic K-RAS mutants. Here, taking advantage of our previous finding that NEDD4-1 is an E3 ubiquitin ligase for wild-type RAS proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-RAS mutants including K-RASG12V, and significantly inhibit proliferation and tumor development of K-RAS mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.
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