Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.042
Wei Xu , Minmin Shen , Junjie Ma , Chuanlin Peng , Shanshan Wu , Xinxin Yang , Jiahe Wu , Youyou Yan , Nengming Lin , Jianqing Gao , Bo Zhang
Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.
{"title":"The cytoskeletal protein smoothelin maintains homologous recombination repair by stabilizing RAD51 in an HUWE1-dependent manner in colorectal cancer","authors":"Wei Xu , Minmin Shen , Junjie Ma , Chuanlin Peng , Shanshan Wu , Xinxin Yang , Jiahe Wu , Youyou Yan , Nengming Lin , Jianqing Gao , Bo Zhang","doi":"10.1016/j.apsb.2025.09.042","DOIUrl":"10.1016/j.apsb.2025.09.042","url":null,"abstract":"<div><div>Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both <em>in vitro</em> and <em>in vivo</em>. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6444-6460"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736612","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.09.006
Yuyi Zheng , Xiaotian Zhang , Xiaoxia Gu , Yongqi Li , Qin Li , Yingli Zhu , Bingbing Dai , Yu Liang , Ruping Fan , Chunmei Chen , Weiguang Sun , Yonghui Zhang , Hucheng Zhu
Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and remains a challenge in its management. Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a promising strategy for future therapeutic approaches. Undulanoids A−D (1−4), four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers, including three all-carbon quaternary centers, two quaternary carbon centers at the bridgehead, and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment, were isolated from Aspergillus undulatus. Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction. Strikingly, undulanoid B (2), the most promising lead compound, inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways. Furthermore, reverse target prediction, cellular thermal shift assay, and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation. As the pioneering S100A8/A9 complex and inhibit its secretion. Moreover, compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation. As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex, this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.
{"title":"Undulanoids A−D: Unexpected sesterterpenoids as potent S100A8/A9 complex inhibitors for psoriasis treatment","authors":"Yuyi Zheng , Xiaotian Zhang , Xiaoxia Gu , Yongqi Li , Qin Li , Yingli Zhu , Bingbing Dai , Yu Liang , Ruping Fan , Chunmei Chen , Weiguang Sun , Yonghui Zhang , Hucheng Zhu","doi":"10.1016/j.apsb.2025.09.006","DOIUrl":"10.1016/j.apsb.2025.09.006","url":null,"abstract":"<div><div>Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and remains a challenge in its management. Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a promising strategy for future therapeutic approaches. Undulanoids A−D (<strong>1</strong>−<strong>4</strong>), four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers, including three all-carbon quaternary centers, two quaternary carbon centers at the bridgehead, and a 1,4,11-trimethyltricyclo[5.3.1.0<sup>4,11</sup>]undecane fragment, were isolated from <em>Aspergillus undulatus</em>. Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction. Strikingly, undulanoid B (<strong>2</strong>), the most promising lead compound, inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways. Furthermore, reverse target prediction, cellular thermal shift assay, and dynamic simulation indicated that compound <strong>2</strong> could target with the expression of S100A9 and keratinocyte proliferation. As the pioneering S100A8/A9 complex and inhibit its secretion. Moreover, compound <strong>2</strong> showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation. As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex, this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6495-6509"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736081","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.09.040
Wanzhuo He , Tian Xu , Miao Wang , Ni Ni , Yun Su , Xianqun Fan
Bone defects, characterized by a loss of skeletal structure integrity, represent a prevalent clinical challenge affecting millions of patients. While bone autografts and allografts offer potential solutions, limitations, including donor scarcity, immune rejection, anatomical constraints, and complications arising from host comorbidities such as diabetes, often lead to unsatisfactory outcomes. This necessitates the need for alternative treatments. Researchers have identified that reactive oxygen species (ROS) play a crucial role in bone regeneration. Although physiological ROS levels are essential for normal healing, excessive ROS accumulation disrupts the balance between bone formation and resorption, hindering regeneration. Antioxidants can mitigate oxidative stress by scavenging ROS or inhibiting their formation, thereby restoring the equilibrium between bone formation and resorption. Advances in nanotechnology have enabled the development of various ROS-scavenging nanomaterials with enhanced therapeutic efficacy. These nanomaterials either function as delivery platforms for conventional antioxidants or as direct ROS-neutralizing agents through intrinsic redox or enzyme-mimicking properties. This review comprehensively summarizes ROS-scavenging nanomaterials for bone tissue regeneration, focusing on their design strategies, underlying mechanisms, applications, and potential for clinical translation.
{"title":"ROS-scavenging nanomaterials as emerging tools for bone tissue regeneration: A comprehensive review of recent progress","authors":"Wanzhuo He , Tian Xu , Miao Wang , Ni Ni , Yun Su , Xianqun Fan","doi":"10.1016/j.apsb.2025.09.040","DOIUrl":"10.1016/j.apsb.2025.09.040","url":null,"abstract":"<div><div>Bone defects, characterized by a loss of skeletal structure integrity, represent a prevalent clinical challenge affecting millions of patients. While bone autografts and allografts offer potential solutions, limitations, including donor scarcity, immune rejection, anatomical constraints, and complications arising from host comorbidities such as diabetes, often lead to unsatisfactory outcomes. This necessitates the need for alternative treatments. Researchers have identified that reactive oxygen species (ROS) play a crucial role in bone regeneration. Although physiological ROS levels are essential for normal healing, excessive ROS accumulation disrupts the balance between bone formation and resorption, hindering regeneration. Antioxidants can mitigate oxidative stress by scavenging ROS or inhibiting their formation, thereby restoring the equilibrium between bone formation and resorption. Advances in nanotechnology have enabled the development of various ROS-scavenging nanomaterials with enhanced therapeutic efficacy. These nanomaterials either function as delivery platforms for conventional antioxidants or as direct ROS-neutralizing agents through intrinsic redox or enzyme-mimicking properties. This review comprehensively summarizes ROS-scavenging nanomaterials for bone tissue regeneration, focusing on their design strategies, underlying mechanisms, applications, and potential for clinical translation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6274-6306"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736068","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.10.010
Lipeng Tang , Guanzhuo Li , Jiameng Chang , Haiyan Xian , Yanjie Liu , Luping Lin , Zixin Dai , Zhenting Liu , Xinmin Qiu , Bowen Zhang , Zuqing Su , Bing Feng , Ying Zhu , Maojie Wang , Yuchao Chen , Huazhen Liu , Dinghong Wu , Chutian Li , Jie Zhao , Mingxian Li , Guangjuan Zheng
Psoriasis is a common inflammatory skin disease with characterization of epidermal hyperplasia and sustained skin inflammation. Long noncoding RNAs (lncRNAs), which contain more than 200 nucleotide-long transcripts, are emerging as the crux of epigenetic regulators in multiple biological processes and diseases. However, how lncRNAs contribute to the etiology of psoriasis remains to be elucidated. For the first time, this study revealed that SNHG15, which was elevated in cytokines-stimulated keratinocytes and psoriasis lesions, promoted keratinocytes hyperproliferation. Mechanistically, SNHG15 fueled epithelial pathology through activation of STAT3/Cyclin D1 axis. Intriguingly, activation of STAT3 enhanced SNHG15 transcription to form a positive feed-back modulatory loop and consequently augmented the skin lesions in psoriasis. Furthermore, knock down the expression of SNHG15 can counteract the IMQ-induced keratinocytes hyperproliferation in vivo. Taken together, our findings uncover that SNHG15 facilitates epidermal hyperplasia via STAT3/Cyclin D1 axis, which might provide a novel therapeutic avenue for psoriasis treatment.
{"title":"Elevated SNHG15 empowers keratinocytes hyperproliferation through activation of STAT3/Cyclin D1 axis in psoriasis","authors":"Lipeng Tang , Guanzhuo Li , Jiameng Chang , Haiyan Xian , Yanjie Liu , Luping Lin , Zixin Dai , Zhenting Liu , Xinmin Qiu , Bowen Zhang , Zuqing Su , Bing Feng , Ying Zhu , Maojie Wang , Yuchao Chen , Huazhen Liu , Dinghong Wu , Chutian Li , Jie Zhao , Mingxian Li , Guangjuan Zheng","doi":"10.1016/j.apsb.2025.10.010","DOIUrl":"10.1016/j.apsb.2025.10.010","url":null,"abstract":"<div><div>Psoriasis is a common inflammatory skin disease with characterization of epidermal hyperplasia and sustained skin inflammation. Long noncoding RNAs (lncRNAs), which contain more than 200 nucleotide-long transcripts, are emerging as the crux of epigenetic regulators in multiple biological processes and diseases. However, how lncRNAs contribute to the etiology of psoriasis remains to be elucidated. For the first time, this study revealed that SNHG15, which was elevated in cytokines-stimulated keratinocytes and psoriasis lesions, promoted keratinocytes hyperproliferation. Mechanistically, SNHG15 fueled epithelial pathology through activation of STAT3/Cyclin D1 axis. Intriguingly, activation of STAT3 enhanced SNHG15 transcription to form a positive feed-back modulatory loop and consequently augmented the skin lesions in psoriasis. Furthermore, knock down the expression of SNHG15 can counteract the IMQ-induced keratinocytes hyperproliferation <em>in vivo</em>. Taken together, our findings uncover that SNHG15 facilitates epidermal hyperplasia <em>via</em> STAT3/Cyclin D1 axis, which might provide a novel therapeutic avenue for psoriasis treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6430-6443"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736611","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.10.011
Rui Wang, Chunlin Zhuang
Graph neural networks (GNNs) are revolutionizing drug design processes. Over the past five years, GNNs have emerged as transformative tools by accurately modeling molecular structures and interactions with binding targets. Breakthroughs in predicting molecular properties, drug repurposing, toxicity assessment, and interaction analysis, along with generative GNNs enhancing virtual screening and novel molecule design, have significantly sped up drug discovery. These GNN-driven innovations improve predictive accuracy, cut development costs, and reduce late-stage failures. This review focuses on the interdisciplinary integration of GNNs throughout the discovery process, including lead discovery and optimization, synthetic route design, drug–target interaction prediction, and molecular property profiling, while critically evaluating the challenges in translational medicine.
{"title":"Graph neural networks driven acceleration in drug discovery","authors":"Rui Wang, Chunlin Zhuang","doi":"10.1016/j.apsb.2025.10.011","DOIUrl":"10.1016/j.apsb.2025.10.011","url":null,"abstract":"<div><div>Graph neural networks (GNNs) are revolutionizing drug design processes. Over the past five years, GNNs have emerged as transformative tools by accurately modeling molecular structures and interactions with binding targets. Breakthroughs in predicting molecular properties, drug repurposing, toxicity assessment, and interaction analysis, along with generative GNNs enhancing virtual screening and novel molecule design, have significantly sped up drug discovery. These GNN-driven innovations improve predictive accuracy, cut development costs, and reduce late-stage failures. This review focuses on the interdisciplinary integration of GNNs throughout the discovery process, including lead discovery and optimization, synthetic route design, drug–target interaction prediction, and molecular property profiling, while critically evaluating the challenges in translational medicine.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6163-6177"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736080","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.10.026
Mengyang Liu , Darren Svirskis , Thomas Proft , Jacelyn Loh , Naibo Yin , Hao Li , Danhui Li , Yongzhi Zhou , Shuo Chen , Lizhuo Song , Guanyu Chen , Wei-Yue Lu , Zhiwen Zhang , Zhou Zhou , Lian Li , Yuan Huang , Craig Bunt , Guiju Sun , Paul W.R. Harris , Margaret A. Brimble , Jingyuan Wen
Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.
{"title":"Progress in peptide and protein therapeutics: Challenges and strategies","authors":"Mengyang Liu , Darren Svirskis , Thomas Proft , Jacelyn Loh , Naibo Yin , Hao Li , Danhui Li , Yongzhi Zhou , Shuo Chen , Lizhuo Song , Guanyu Chen , Wei-Yue Lu , Zhiwen Zhang , Zhou Zhou , Lian Li , Yuan Huang , Craig Bunt , Guiju Sun , Paul W.R. Harris , Margaret A. Brimble , Jingyuan Wen","doi":"10.1016/j.apsb.2025.10.026","DOIUrl":"10.1016/j.apsb.2025.10.026","url":null,"abstract":"<div><div>Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6342-6381"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736662","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 : 2025-12-01DOI: 10.1016/j.apsb.2025.08.013
Xuanlin Su , Jiankun Zang , Yaping Wang , Shiqing Zhang , Panwen Wu , Wei Chen , Lei Shi , Yousheng Wu , Die Deng , Kaiwei Cai , Hongcheng Mai , Anding Xu , Dan Lu
The ischemic penumbra is critical in acute ischemic stroke (AIS) treatment, yet the regulation of precise RNA modification pathways remains unclear. Using a mouse model of ischemic stroke and human postmortem brain samples, we demonstrate that N6-methyladenosine (m6A) levels are elevated in neurons within the ischemic penumbra. Notably, m6A modifications by m6A reader protein IGF2BP1 were enriched on penumbra related circular RNA derived from oxoglutarate dehydrogenase (CircOGDH). IGF2BP1 stabilizes CircOGDH by recruiting it to stress granules, maintaining high expression in the ischemic penumbra. Knockdown of IGF2BP1 reduced CircOGDH stability and decreased neuronal apoptosis under hypoxic conditions, suggesting a protective role. Igf2bp1 knockdown also preserved synaptic integrity in MCAO mice, with increased expression of synaptic markers and improved synaptic morphology. Importantly, Igf2bp1 knockdown significantly reduced penumbra volume compared to CircOGDH inhibition alone. These findings highlight IGF2BP1 as a promising therapeutic target for modulating penumbra-related RNA expression and promoting recovery in AIS.
{"title":"IGF2BP1 positively regulates CircOGDH accumulation in hypoxia induced stress granules","authors":"Xuanlin Su , Jiankun Zang , Yaping Wang , Shiqing Zhang , Panwen Wu , Wei Chen , Lei Shi , Yousheng Wu , Die Deng , Kaiwei Cai , Hongcheng Mai , Anding Xu , Dan Lu","doi":"10.1016/j.apsb.2025.08.013","DOIUrl":"10.1016/j.apsb.2025.08.013","url":null,"abstract":"<div><div>The ischemic penumbra is critical in acute ischemic stroke (AIS) treatment, yet the regulation of precise RNA modification pathways remains unclear. Using a mouse model of ischemic stroke and human postmortem brain samples, we demonstrate that <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) levels are elevated in neurons within the ischemic penumbra. Notably, m<sup>6</sup>A modifications by m<sup>6</sup>A reader protein IGF2BP1 were enriched on penumbra related circular RNA derived from oxoglutarate dehydrogenase (CircOGDH). IGF2BP1 stabilizes CircOGDH by recruiting it to stress granules, maintaining high expression in the ischemic penumbra. Knockdown of IGF2BP1 reduced CircOGDH stability and decreased neuronal apoptosis under hypoxic conditions, suggesting a protective role. <em>Igf2bp1</em> knockdown also preserved synaptic integrity in MCAO mice, with increased expression of synaptic markers and improved synaptic morphology. Importantly, <em>Igf2bp1</em> knockdown significantly reduced penumbra volume compared to CircOGDH inhibition alone. These findings highlight IGF2BP1 as a promising therapeutic target for modulating penumbra-related RNA expression and promoting recovery in AIS.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6478-6494"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736079","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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