Osteoarthritis (OA) presents significant therapeutic challenges due to the irreversible cartilage loss driven by chondrocyte metabolic imbalance and a severe inflammatory microenvironment. Conventional treatments are limited by poor chondrocyte-targeting and ineffectiveness of single-target medication. Here, we develop an anti-inflammatory neutrophil-derived microvesicle (MV)-based gene therapy for OA treatment, which leverages the intrinsic cartilage-penetrating capabilities of MVs to improve the targeted delivery of microRNA-140-5p (miR140) to chondrocytes, and the synergistic effect of anti-inflammatory MVs and miR140 to dual modulate the metabolic homeostasis of chondrocytes and the inflamed microenvironment. We demonstrate that miR140@MVs not only alleviate synovial inflammation via reprogramming the phenotypes of macrophages and adsorbing inflammatory factors, but also restore normal cartilage thickness in a destabilized medial meniscus mouse model due to the rebuilt metabolic homeostasis of chondrocytes, thus gaining a remarkable therapeutic effect up to 28 days. This study provides an immuno-stimulation method for production of anti-inflammatory MVs, and puts forward a safe and effective MVs-based miRNA system for treatment of joint-related diseases.
{"title":"Dual metabolic-inflammation modulation in MicroRNA@neutrophil-derived microvesicles achieve robust osteoarthritis therapy","authors":"Yijun Chen, Yongbin Wang, Ruonan Yan, Yichen Liu, Yupeng Dai, Lingjing Xue, Caoyun Ju, Can Zhang","doi":"10.1016/j.apsb.2025.09.020","DOIUrl":"10.1016/j.apsb.2025.09.020","url":null,"abstract":"<div><div>Osteoarthritis (OA) presents significant therapeutic challenges due to the irreversible cartilage loss driven by chondrocyte metabolic imbalance and a severe inflammatory microenvironment. Conventional treatments are limited by poor chondrocyte-targeting and ineffectiveness of single-target medication. Here, we develop an anti-inflammatory neutrophil-derived microvesicle (MV)-based gene therapy for OA treatment, which leverages the intrinsic cartilage-penetrating capabilities of MVs to improve the targeted delivery of microRNA-140-5p (miR140) to chondrocytes, and the synergistic effect of anti-inflammatory MVs and miR140 to dual modulate the metabolic homeostasis of chondrocytes and the inflamed microenvironment. We demonstrate that miR140@MVs not only alleviate synovial inflammation <em>via</em> reprogramming the phenotypes of macrophages and adsorbing inflammatory factors, but also restore normal cartilage thickness in a destabilized medial meniscus mouse model due to the rebuilt metabolic homeostasis of chondrocytes, thus gaining a remarkable therapeutic effect up to 28 days. This study provides an immuno-stimulation method for production of anti-inflammatory MVs, and puts forward a safe and effective MVs-based miRNA system for treatment of joint-related diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 423-443"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941531","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: 2026-01-10DOI: 10.1016/j.apsb.2025.12.022
Olabisi Coker, Jun Yu
{"title":"Commentary on \"Neg-entropy is the true drug target for chronic diseases\"","authors":"Olabisi Coker, Jun Yu","doi":"10.1016/j.apsb.2025.12.022","DOIUrl":"10.1016/j.apsb.2025.12.022","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 656-657"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941469","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.2025.10.018
Yajun Wang , Ming Zhang , Wei Li
The burden imposed by central nervous system disorders (CNSD) on global health is substantial, characterized by a significant impact on quality of life, increased mortality rates, and escalating economic costs. Glial cells, primarily comprising astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs, also known as NG2 cells), play crucial and diverse roles in neurological health and disease. In the treatment of CNSD with traditional herbal medicines, ginseng and its active components have made a notable impression. This comprehensive review investigates the interaction between ginseng and these essential glial cells, detailing their contributions to neurological well-being and disease states. Additionally, it thoroughly assesses the effects of ginseng on glial function, highlighting its neuroprotective potential through anti-inflammatory, antioxidative, and other restorative actions via complex molecular pathways. Moreover, the review analyzes how ginseng can facilitate neuronal viability and regeneration, as well as modulate signaling cascades, thereby highlighting the therapeutic potential of ginseng in the management of CNSD.
{"title":"Targeting glial cells: Unveiling the neuroprotective mechanisms of Ginseng in the brain microenvironment","authors":"Yajun Wang , Ming Zhang , Wei Li","doi":"10.1016/j.apsb.2025.10.018","DOIUrl":"10.1016/j.apsb.2025.10.018","url":null,"abstract":"<div><div>The burden imposed by central nervous system disorders (CNSD) on global health is substantial, characterized by a significant impact on quality of life, increased mortality rates, and escalating economic costs. Glial cells, primarily comprising astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs, also known as NG2 cells), play crucial and diverse roles in neurological health and disease. In the treatment of CNSD with traditional herbal medicines, ginseng and its active components have made a notable impression. This comprehensive review investigates the interaction between ginseng and these essential glial cells, detailing their contributions to neurological well-being and disease states. Additionally, it thoroughly assesses the effects of ginseng on glial function, highlighting its neuroprotective potential through anti-inflammatory, antioxidative, and other restorative actions <em>via</em> complex molecular pathways. Moreover, the review analyzes how ginseng can facilitate neuronal viability and regeneration, as well as modulate signaling cascades, thereby highlighting the therapeutic potential of ginseng in the management of CNSD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 13-34"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941474","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: 2025-08-27DOI: 10.1016/j.apsb.2025.08.019
Aihua Jin , Nuoya Wang , Yanhong Liu , Shuangqing Wang , Liqing Chen , Liming Gong , Wei Huang , Zhonggao Gao , Mingji Jin
Due to the invasive growth of glioblastomas (GBM) and their resistance to conventional chemotherapy, the efficacy of GBM treatment remains limited. Biomimetic BBB-penetrating hybrid nanovehicles, engineered through homologous cell membrane fusion between cancer cells and protein corona (PC)-mediated liposomes coated with cancer cell membranes, have been explored for brain-targeted drug delivery. In this study, T10 peptide-modified cell membrane-coated liposomes were used to construct an in situ transferrin (Tf) PC-mediated lipo-complex carrying a respiratory depressant agent (metformin, MET) and a photosensitizer (Chlorin, Ce6), creating a transferrin- and cancer cell-targeting delivery system (MET/Ce6@Lipo@CM@T10). MET/Ce6@Lipo@CM@T10 possesses a spherical core–shell structure with uniform distribution while maintaining low systemic toxicity. Upon irradiation, MET/Ce6@Lipo@CM@T10 effectively inhibited cell proliferation and induced apoptosis via photodynamic therapy (PDT). Simultaneously, the loaded MET alleviated intracellular hypoxia caused by PDT, thereby enhancing anti-tumor efficacy. The establishment of an in vitro BBB model and 3D tumor spheroid experiments confirmed that MET/Ce6@Lipo@CM@T10 effectively crossed BBB and deeply accumulated within tumor tissues. As a result, in in vivo animal experiments, MET/Ce6@Lipo@CM@T10 significantly inhibited tumor growth, promoted tumor necrosis and apoptosis, and demonstrated systemic safety. In conclusion, MET/Ce6@Lipo@CM@T10 demonstrated enhanced PDT effects on GBM, and will provide new insights and methods for GBM treatment.
{"title":"Endogenic transferrin-targeted cell membrane-coated biomimetic lipo-complexes for efficient targeting and enhanced antitumor efficacy in orthotopic glioblastoma","authors":"Aihua Jin , Nuoya Wang , Yanhong Liu , Shuangqing Wang , Liqing Chen , Liming Gong , Wei Huang , Zhonggao Gao , Mingji Jin","doi":"10.1016/j.apsb.2025.08.019","DOIUrl":"10.1016/j.apsb.2025.08.019","url":null,"abstract":"<div><div>Due to the invasive growth of glioblastomas (GBM) and their resistance to conventional chemotherapy, the efficacy of GBM treatment remains limited. Biomimetic BBB-penetrating hybrid nanovehicles, engineered through homologous cell membrane fusion between cancer cells and protein corona (PC)-mediated liposomes coated with cancer cell membranes, have been explored for brain-targeted drug delivery. In this study, T<sub>10</sub> peptide-modified cell membrane-coated liposomes were used to construct an <em>in situ</em> transferrin (Tf) PC-mediated lipo-complex carrying a respiratory depressant agent (metformin, MET) and a photosensitizer (Chlorin, Ce6), creating a transferrin- and cancer cell-targeting delivery system (MET/Ce6@Lipo@CM@T<sub>10</sub>). MET/Ce6@Lipo@CM@T<sub>10</sub> possesses a spherical core–shell structure with uniform distribution while maintaining low systemic toxicity. Upon irradiation, MET/Ce6@Lipo@CM@T<sub>10</sub> effectively inhibited cell proliferation and induced apoptosis <em>via</em> photodynamic therapy (PDT). Simultaneously, the loaded MET alleviated intracellular hypoxia caused by PDT, thereby enhancing anti-tumor efficacy. The establishment of an <em>in vitro</em> BBB model and 3D tumor spheroid experiments confirmed that MET/Ce6@Lipo@CM@T<sub>10</sub> effectively crossed BBB and deeply accumulated within tumor tissues. As a result, in <em>in vivo</em> animal experiments, MET/Ce6@Lipo@CM@T<sub>10</sub> significantly inhibited tumor growth, promoted tumor necrosis and apoptosis, and demonstrated systemic safety. In conclusion, MET/Ce6@Lipo@CM@T<sub>10</sub> demonstrated enhanced PDT effects on GBM, and will provide new insights and methods for GBM treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 574-595"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941500","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: 2025-09-17DOI: 10.1016/j.apsb.2025.09.025
Minju Han , Eunji Kim , Minchan Jeong , Solbi Kim , Hyo-Jin Lee , Heung Jin Jeon
The tumor microenvironment is characterized by an immunosuppressive state. Although PD-1/PD-L1 blockade therapy activates the immune system against tumors, it has limited long-term efficacy, prompting the development of combination therapies with targeted treatments to improve cancer treatment outcomes. Recent advancements have revitalized interest in using attenuated Salmonella strains as cancer therapeutics that target tumors, induce immune responses, and promote tumor cell death, although complete tumor suppression remains challenging. We aimed to induce antitumor effects by activating the suppressed immune system within the tumor microenvironment using Salmonella-mediated secretion of interleukin-21 (IL-21). We used the tumor-targeting ability of Salmonella and its flagellar type-3 secretion system (FT3SS) to induce the secretion of IL-21 into the tumor microenvironment via the flagellar system and evaluated the local immune response. We also evaluated the efficacy of combining Salmonella-mediated IL-21 delivery and anti-PD-L1 therapy in a mouse model. IL-21 secretion promoted the recruitment of CD4+ and CD8+ T cells and enhanced the expression of cytotoxicity-related molecules. Tumor-bearing mice treated with the combination therapy with anti-PD-L1 antibodies showed improved survival rates and enhanced tumor growth inhibition. This study demonstrates the tumor-targeting capability and in vivo safety of Salmonella, highlighting its potential as a powerful cancer therapy platform.
{"title":"Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects","authors":"Minju Han , Eunji Kim , Minchan Jeong , Solbi Kim , Hyo-Jin Lee , Heung Jin Jeon","doi":"10.1016/j.apsb.2025.09.025","DOIUrl":"10.1016/j.apsb.2025.09.025","url":null,"abstract":"<div><div>The tumor microenvironment is characterized by an immunosuppressive state. Although PD-1/PD-L1 blockade therapy activates the immune system against tumors, it has limited long-term efficacy, prompting the development of combination therapies with targeted treatments to improve cancer treatment outcomes. Recent advancements have revitalized interest in using attenuated <em>Salmonella</em> strains as cancer therapeutics that target tumors, induce immune responses, and promote tumor cell death, although complete tumor suppression remains challenging. We aimed to induce antitumor effects by activating the suppressed immune system within the tumor microenvironment using <em>Salmonella</em>-mediated secretion of interleukin-21 (IL-21). We used the tumor-targeting ability of <em>Salmonella</em> and its flagellar type-3 secretion system (FT3SS) to induce the secretion of IL-21 into the tumor microenvironment <em>via</em> the flagellar system and evaluated the local immune response. We also evaluated the efficacy of combining <em>Salmonella</em>-mediated IL-21 delivery and anti-PD-L1 therapy in a mouse model. IL-21 secretion promoted the recruitment of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and enhanced the expression of cytotoxicity-related molecules. Tumor-bearing mice treated with the combination therapy with anti-PD-L1 antibodies showed improved survival rates and enhanced tumor growth inhibition. This study demonstrates the tumor-targeting capability and <em>in vivo</em> safety of <em>Salmonella</em>, highlighting its potential as a powerful cancer therapy platform.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 239-251"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941390","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: 2025-09-12DOI: 10.1016/j.apsb.2025.09.014
Qi Shang , Chenwei Jiang , Xiaolong Wang , Mingmei Guo , Jing Liu , Zhedong Jin , Yunsheng Yuan , Feihu Wang
Vaccines represent one of the most potent strategies for protecting humans from the threat of infectious diseases. Conventional vaccines elicit acquired immunity by mimicking pathogen characteristics; however, their protective efficacy is limited by inadequate spatiotemporal control of antigen delivery, resulting in suboptimal antigen exposure in lymphoid tissues and transient adaptive immune activation. Here, we developed a self-assembling peptide-based supramolecular hydrogel vaccine to establish a localized immune niche, demonstrating its remarkable efficacy in inducing durable and potent immunity against infectious diseases. We found that this in situ-formed supramolecular hydrogel vaccine serves as a reservoir for antigens and adjuvants while recruiting antigen-presenting dendritic cells (DCs) to accumulate within the scaffold. With the aid of adjuvant, the DCs exhibit enhanced antigen processing and presentation, creating an immunologically active niche that triggers robust B cell and T cell responses. Following a single vaccination, mice immunized with the hydrogel vaccine developed robust humoral immunity and sustained antibody production for 112 days, achieving potent neutralization activity. This study offers a novel approach to spatiotemporal control of vaccine responses that enables durable and enhanced immunity against infectious diseases.
{"title":"Construction of a localized immune niche via supramolecular hydrogel vaccine to elicit durable and enhanced immunity against infectious diseases","authors":"Qi Shang , Chenwei Jiang , Xiaolong Wang , Mingmei Guo , Jing Liu , Zhedong Jin , Yunsheng Yuan , Feihu Wang","doi":"10.1016/j.apsb.2025.09.014","DOIUrl":"10.1016/j.apsb.2025.09.014","url":null,"abstract":"<div><div>Vaccines represent one of the most potent strategies for protecting humans from the threat of infectious diseases. Conventional vaccines elicit acquired immunity by mimicking pathogen characteristics; however, their protective efficacy is limited by inadequate spatiotemporal control of antigen delivery, resulting in suboptimal antigen exposure in lymphoid tissues and transient adaptive immune activation. Here, we developed a self-assembling peptide-based supramolecular hydrogel vaccine to establish a localized immune niche, demonstrating its remarkable efficacy in inducing durable and potent immunity against infectious diseases. We found that this <em>in situ</em>-formed supramolecular hydrogel vaccine serves as a reservoir for antigens and adjuvants while recruiting antigen-presenting dendritic cells (DCs) to accumulate within the scaffold. With the aid of adjuvant, the DCs exhibit enhanced antigen processing and presentation, creating an immunologically active niche that triggers robust B cell and T cell responses. Following a single vaccination, mice immunized with the hydrogel vaccine developed robust humoral immunity and sustained antibody production for 112 days, achieving potent neutralization activity. This study offers a novel approach to spatiotemporal control of vaccine responses that enables durable and enhanced immunity against infectious diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 470-483"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941494","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: 2025-11-04DOI: 10.1016/j.apsb.2025.10.048
Haiyan Wang , Zhi-Chao Sun , Chunlei Dai , Ran Liao , Ran Lin , Liying Wang , Wenjun Fu , Ruhe Zhang , Danwen Zheng , Zhongde Zhang , Jun Wu , Yuntao Liu
Acute respiratory distress syndrome (ARDS) is a life-threatening disease. In the clinical management of ARDS, current treatments such as glucocorticoids and protease inhibitors encounter significant challenges due to their high toxicity, limited administration routes, or poor targeting. These limitations highlight the urgent need for innovative therapeutic strategies. Songorine (Son), a compound derived from the herb Aconitum carmichaelii Debeaux, possesses good antioxidant and anti-inflammatory properties, exhibiting great potential for treating ARDS. However, its clinical application is partially constrained by low aqueous solubility and uncertain efficacy for ARDS. In this study, we developed a lung-targeted lipid nanomedicine by encapsulating Son in dipalmitoyl phosphatidylcholine (DPPC) liposomes (Son@liposome, Son-lipo). In a lipopolysaccharide-induced ARDS mouse model, we demonstrated that Son-lipo effectively targeted inflamed lung tissues with commendable biocompatibility. Further, Son-lipo significantly alleviated multiple ARDS phenotypes such as endothelial barrier damage, lung edema, pulmonary dysfunction, and alveolar lesion, which involved uncontrolled inflammation, oxidative stress, and cell apoptosis. RNA sequencing and Western blotting analyses revealed that Son-lipo inhibited the activation of the TLR4/NF-κB/NLRP3 pathway responsible for ARDS. In conclusion, our study successfully developed an inhalable lipid-nanomedicine (Son-lipo) as a novel therapeutic strategy for ARDS. It elucidates the formulation's ability to mitigate ARDS by repairing the endothelial barrier and reversing the inflammatory microenvironment, thereby providing a promising candidate drug for improving clinical management of ARDS.
{"title":"Inhalable songorine-integrated lipid nanomedicine for targeted ARDS therapy via repairing endothelial barrier and inactivating NLRP3 inflammasome","authors":"Haiyan Wang , Zhi-Chao Sun , Chunlei Dai , Ran Liao , Ran Lin , Liying Wang , Wenjun Fu , Ruhe Zhang , Danwen Zheng , Zhongde Zhang , Jun Wu , Yuntao Liu","doi":"10.1016/j.apsb.2025.10.048","DOIUrl":"10.1016/j.apsb.2025.10.048","url":null,"abstract":"<div><div>Acute respiratory distress syndrome (ARDS) is a life-threatening disease. In the clinical management of ARDS, current treatments such as glucocorticoids and protease inhibitors encounter significant challenges due to their high toxicity, limited administration routes, or poor targeting. These limitations highlight the urgent need for innovative therapeutic strategies. Songorine (Son), a compound derived from the herb <em>Aconitum carmichaelii</em> Debeaux, possesses good antioxidant and anti-inflammatory properties, exhibiting great potential for treating ARDS. However, its clinical application is partially constrained by low aqueous solubility and uncertain efficacy for ARDS. In this study, we developed a lung-targeted lipid nanomedicine by encapsulating Son in dipalmitoyl phosphatidylcholine (DPPC) liposomes (Son@liposome, Son-lipo). In a lipopolysaccharide-induced ARDS mouse model, we demonstrated that Son-lipo effectively targeted inflamed lung tissues with commendable biocompatibility. Further, Son-lipo significantly alleviated multiple ARDS phenotypes such as endothelial barrier damage, lung edema, pulmonary dysfunction, and alveolar lesion, which involved uncontrolled inflammation, oxidative stress, and cell apoptosis. RNA sequencing and Western blotting analyses revealed that Son-lipo inhibited the activation of the TLR4/NF-<em>κ</em>B/NLRP3 pathway responsible for ARDS. In conclusion, our study successfully developed an inhalable lipid-nanomedicine (Son-lipo) as a novel therapeutic strategy for ARDS. It elucidates the formulation's ability to mitigate ARDS by repairing the endothelial barrier and reversing the inflammatory microenvironment, thereby providing a promising candidate drug for improving clinical management of ARDS.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 596-615"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941501","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: 2025-10-25DOI: 10.1016/j.apsb.2025.10.020
Huanhuan Pang , Honglin Chen , Peng Chen , Xu Wei , Hongda Liu , Xueling He , Yang Yang , Junzhe Zhang , Dianfei Li , Linlin Lou , Wen Xie , Chong Qiu , Fei Xia , Qiuyan Guo , Shengnan Shen , Qiaoli Shi , Weiguang Li , Guang Han , Xijun Wang , Jigang Wang , Chengchao Xu
Sepsis is a life-threatening disease caused by the dysregulated host immune response to infection, which eventually leads to multi-organ failure. Current therapeutic strategies rely heavily on antibiotics. However, conventional antimicrobial therapy often leads to antibiotic abuse and resistance. Therefore, it is of utmost importance to develop new agents for treating sepsis. Here, we demonstrated that gambogenic acid (GNA) not only restricted the release of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages but also attenuated the inflammatory response and organ damage in septic mice. By using the activity-based protein profiling (ABPP) strategy, we identified 30 potential target proteins of GNA. Among these potential targets, we found that GNA directly bound to the Cys684 residue of hexokinase 1 (HK1) and affected its enzyme activity and cellular localization. These findings were confirmed by the cellular thermal shift assay (CETSA), bio-layer interferometry (BLI), and single-site mutation experiments. Functionally, siHK1 alleviated the Warburg effect, suppressed the activation of NLRP3 inflammasome, and eventually suppressed the release of inflammatory cytokines. Taken together, our findings demonstrated that GNA could attenuate inflammation by alleviating HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis and could serve as a novel therapeutic agent for sepsis and inflammatory disorders.
{"title":"Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis","authors":"Huanhuan Pang , Honglin Chen , Peng Chen , Xu Wei , Hongda Liu , Xueling He , Yang Yang , Junzhe Zhang , Dianfei Li , Linlin Lou , Wen Xie , Chong Qiu , Fei Xia , Qiuyan Guo , Shengnan Shen , Qiaoli Shi , Weiguang Li , Guang Han , Xijun Wang , Jigang Wang , Chengchao Xu","doi":"10.1016/j.apsb.2025.10.020","DOIUrl":"10.1016/j.apsb.2025.10.020","url":null,"abstract":"<div><div>Sepsis is a life-threatening disease caused by the dysregulated host immune response to infection, which eventually leads to multi-organ failure. Current therapeutic strategies rely heavily on antibiotics. However, conventional antimicrobial therapy often leads to antibiotic abuse and resistance. Therefore, it is of utmost importance to develop new agents for treating sepsis. Here, we demonstrated that gambogenic acid (GNA) not only restricted the release of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages but also attenuated the inflammatory response and organ damage in septic mice. By using the activity-based protein profiling (ABPP) strategy, we identified 30 potential target proteins of GNA. Among these potential targets, we found that GNA directly bound to the Cys684 residue of hexokinase 1 (HK1) and affected its enzyme activity and cellular localization. These findings were confirmed by the cellular thermal shift assay (CETSA), bio-layer interferometry (BLI), and single-site mutation experiments. Functionally, siHK1 alleviated the Warburg effect, suppressed the activation of NLRP3 inflammasome, and eventually suppressed the release of inflammatory cytokines. Taken together, our findings demonstrated that GNA could attenuate inflammation by alleviating HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis and could serve as a novel therapeutic agent for sepsis and inflammatory disorders.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 337-351"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941526","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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