Nature Communications
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2025
·Vol. 16
·期 1
·1-17
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IF 15.7
Zheng Haiyan,Zhang Lu,Bai Xinning,Zhu Jinchao,Liu Shanshan,Ke Yao,Lin Qingyuan,Yuan Yuan,Ji Tianhai
Glioblastoma (GBM) is a highly invasive malignancy with a poor prognosis, primarily attributable to its diffuse infiltration into adjacent brain tissue, thereby complicating effective surgical resection. Current imaging modalities often struggle to accurately identify tumor boundaries. Here, we identify general control non-repressed protein 5 (GCN5) as a promising molecular target for GBM imaging, as it is expressed in GBM lesions within brain tissue, and its expression levels are significantly correlated with GBM grading. We develop a dual-modal probe with a particle size of 20 nm, capable of efficiently traversing the blood-brain barrier (BBB) to target GCN5 through adsorptive-mediated transcytosis (AMT). The probe employs dendrimers (Den) as carriers, which are loaded with a small molecule inhibitor specifically designed to target GCN5. This probe enhances the preoperative delineation of GBM boundaries using magnetic resonance imaging (MRI) and facilitates intraoperative fluorescence image-guided surgical procedures. Our work introduces a promising tool for boundary delineation, offering new opportunities for the precise resection of GBM.
研究领域:
医学影像学
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神经肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
Acta Biomaterialia
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2021
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IF 8.947
Ye Yuan,Jia Liu,Xiangnan Yu,Xingxin Liu,Yanni Cheng,Cheng Zhou,Mingyi Li,Lin Shi,Yan Deng,Huan Liu,Guobin Wang,Lin Wang,Zheng Wang
Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/ [email protected] increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance. Statement of significance We designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.
研究领域:
肿瘤学
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药学
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纳米技术
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表观遗传学
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DOI
PubMed
高影响因子
Nature Communications
·
2026
·Vol. 17
·期 1
·2821
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IF 18.1
Xiao Hai-Tao,Song Peng,Jin Jing,Wang Yong-Dan,Xu Yin-Yue,Wu He,Shao Xue-Xue,Gan Qi-Feng,He Jian,Wen Yan-Rong,Zhu Jing,Chen Bao-Yi,Zhou Ping,Lai Li-Na,Yang Hua,Li Ping,Zheng Zu-Guo
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern that affects nearly one-quarter of the world’s population. General control non-repressed protein 5 (GCN5), a histone acetyltransferase (HAT), has been implicated in the progression of several diseases, but its role in MASLD remains unclear. Here, we provide the experimental evidence that progressive human and male murine MASLD is driven by GCN5, but not by p300/CREB binding protein associated factor (PCAF) activation. Hepatocyte-specific GCN5 overexpression accelerates MASLD progression, whereas its ablation alleviates disease severity. Moreover, pharmacological inhibition of GCN5 with CPTH2 protects against MASLD. Metabolomics and RNA-seq analyses demonstrate that GCN5 promotes de novo lipogenesis (DNL) by upregulating SREBP1c-mediated transcription of lipogenic genes. Mechanistically, GCN5 acetylates histone H3 at the SREBP1c promoter, enhancing transcription through its intrinsic acetyltransferase activity. Our findings further identify GCN5 as a key regulator of LXRα-induced SREBP1c expression, suggesting that targeting GCN5 may selectively inhibit SREBP1c-driven DNL without impairing LXRα-mediated reverse cholesterol transport (RCT). Notably, combined treatment with the Liver X Receptor (LXR) agonist T0901317 and CPTH2 synergistically reduced lipid accumulation in vitro and in vivo, highlighting a promising therapeutic strategy for MASLD.
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DOI
PubMed
高影响因子
Chinese Medicine
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2026
·Vol. 21
·期 1
·223
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IF 7.4
Liang Hui-Mei,Xu Yin-Yue,Miao Kun,Xiao Hai-Tao,Wang Yong-Dan,Jin Jing,Wu He,Chen Bao-Yi,Xu Li-Jun,Zhu Jiang-Ping,Lai Li-Na,Zheng Zu-Guo
Background Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanisms remain unclear. Purpose This study aimed to elucidate how AS-IV alleviates hepatic steatosis, specifically investigating its epigenetic regulation of lipogenesis. Methods Using high-fat diet-fed mice and lipids-loaded hepatocytes, we assessed AS-IV's effects through SREBP-1c overexpression, histone acetylation analysis, and GCN5 rescue experiments. Results AS-IV significantly reduced hepatic steatosis by suppressing SREBP-1c-mediated de novo lipogenesis. Mechanistically, it inhibited histone acetyltransferase GCN5, decreasing H3K9/H3K14 acetylation at the SREBP-1c promoter and attenuating LXRα-driven transcription. GCN5 overexpression reversed AS-IV's suppression of SREBP-1c and lipid accumulation. Conclusion AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.
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高影响因子
Advanced Science
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2025
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IF 14.1
Yaping Yue,Tingting Lu,Xiaoyuan Guo,Biao Liu,Shiteng Lv,Heba A. M. Abdalla,Xuelei Lai,Ruihui Zhang,Jianpin Guo,Yu Zhao,Dao-Xiu Zhou,Shaoli Zhou
SAGA (Spt-Ada-Gcn5 acetyltransferase) is a highly conserved histone acetyltransferase (HAT) complex in eukaryotes, playing a crucial role in regulating gene transcription during development. The complex consists of two core components: GCN5, the HAT subunit, and ADA2, which primarily functions as an adaptor and enhances the complex HAT activity. Beyond its well-established roles, it is discovered in this work that ADA2 in rice possesses a broadly existing intrinsically disordered region (IDR) that directs the formation of nuclear condensates. Moreover, ADA2 is found to interact with a subunit of ATP-citrate lyase (ACL), an enzyme that produces acetyl-CoA, leading to the formation of a GCN5-ADA2-ACL (GAA) complex. ADA2 promotes the condensation of both GCN5 and ACL in vivo. Within these condensates, ACL contributes to the production and enrichment of acetyl-CoA, thereby promoting histone acetylation. Genetic evidence showed that knock-out or suppression of these genes led to similarly diminished root meristem zone sizes and reduced branch primordia numbers, accompanied by significant reductions in genomic H3K9 acetylation and transcriptional attenuation of essential genes for meristem function. In summary, the findings unveil a novel mechanism of HAT action by forming phase separation to enrich acetyl-CoA within nuclear puncta, facilitating histone acetylation at target genes essential for meristem development.
研究领域:
植物生物学
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分子遗传学
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表观遗传学
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发育生物学
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生物化学
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DOI
PubMed
高影响因子
ACS Central Science
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2023
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IF 18.2
Ruoxi Wang,Yu Wang,Yuting Niu,Danqing He,Shanshan Jin,Zixin Li,Lisha Zhu,Liyuan Chen,Xiaolan Wu,Chengye Ding,Tianhao Wu,Xinmeng Shi,He Zhang,Chang Li,Xin Wang,Zhengwei Xie,Weiran Li,Yan Liu
Maintaining the stemness of bone marrow mesenchymal stem cells (BMMSCs) is crucial for bone homeostasis and regeneration. However, in vitro expansion and bone diseases impair BMMSC stemness, limiting its functionality in bone tissue engineering. Using a deep learning-based efficacy prediction system and bone tissue sequencing, we identify a natural small-molecule compound, dihydroartemisinin (DHA), that maintains BMMSC stemness and enhances bone regeneration. During long-term in vitro expansion, DHA preserves BMMSC stemness characteristics, including its self-renewal ability and unbiased differentiation. In an osteoporosis mouse model, oral administration of DHA restores the femur trabecular structure, bone density, and BMMSC stemness in situ. Mechanistically, DHA maintains BMMSC stemness by promoting histone 3 lysine 9 acetylation via GCN5 activation both in vivo and in vitro. Furthermore, the bone-targeted delivery of DHA by mesoporous silica nanoparticles improves its therapeutic efficacy in osteoporosis. Collectively, DHA could be a promising therapeutic agent for treating osteoporosis by maintaining BMMSC stemness.
研究领域:
生物医学工程
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干细胞生物学
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药理学
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组织工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）