Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
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IF 3.9
Sun Honglan,Yang Chao,Yin Xiaoyunqing,Chen Shizhao,Huang Yuqi,Kuang Huifang,Luo Wen
The chronic illness known as oral submucous fibrosis (OSF) results in tissue fibrosis, precancerous lesions, and scarring. It usually manifests itself in the buccal mucosa. It frequently occurs in the buccal mucosa. Von Hippel-Lindau (VHL) is an essential component of E3 ubiquitin ligase complex. The loss of VHL led to reduced fibrotic responses, accompanied by ameliorated fiber deposition. However, the precise impact of VHL on OSF is yet unclear. OSF tissues and normal mucosal tissues were applied to analyze the distinct expression of VHL and histone deacetylase 6 (HDAC6). Oral fibroblasts were treated to arecoline to simulate OSF in vitro, and molecular biological experiments were conducted to identify the role of VHL in buccal mucosa fibroblasts (BMFs). VHL was downregulated and HDAC6 was upregulated in OSF tissues and BMFs. Overexpression of VHL inhibited fibrosis in arecoline-treated BMFs. VHL inhibits the level of HDAC6 by inducing the ubiquitination of HDAC6. Knockdown of HDAC6 reduces the fibrogenic ability of BMFs. Furthermore, overexpression of HDAC6 contributes to the activation of NF-κB signaling in BMFs. HDAC6 selective inhibitor ACY-1215 inhibited the NF-κB signaling pathway. VHL attenuated arecoline-induced OSF by inhibiting the ubiquitination of HDAC6 and blocking NF-κB pathway. As a result, our study offers new perspectives into the discovery of novel tactics that can be employed against OSF.
研究领域:
医学
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分子生物学
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Communications Biology
·
2025
·Vol. 8
·期 1
·1-14
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IF 5.1
Zhou Xiaonan,Jiang Peng,Tan Huangqi,Wang Yanfang,Bai Lunhao
Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage and surrounding tissues. The transcription factor Kruppel-like family factor 9 (KLF9) has been identified as a regulator of tumorigenesis. However, its role in OA is still not fully understood. Herein, this study aimed to access the potential role and molecular mechanism by which KLF9 regulates OA development. KLF9 was upregulated in cartilage tissues of OA patients and medial meniscotibial ligament (MMTL)-induced OA rats, as well as in IL-1β-treated chondrocytes. Furthermore, knockdown of KLF9 inhibited OA-related cartilage injury, as evidenced by inhibiting chondrocyte extracellular matrix (ECM) degradation, increasing chondrocyte viability, and decreasing apoptosis. Conversely, overexpression of KLF9 had the opposite effect. The downstream mechanism of KLF9 was confirmed. KLF9 mediated the transcription of G protein-coupled receptor kinase 5 (GRK5) by directly targeting the GRK5 promoter. GRK5 knockdown eliminated the effects of KLF9 overexpression on chondrocyte dysfunction. It was also found that GRK5 combined with histone deacetylase 6 (HDAC6) and promoted HDAC6 phosphorylation. The use of the HDAC6 inhibitor TubastatinA also abolished the effects of GRK5 overexpression on chondrocyte ECM degradation and apoptosis. These results demonstrate that the KLF9-GRK5-HDAC6 axis plays a crucial role in promoting the progression of OA.
研究领域:
风湿病学
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分子生物学
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医学遗传学
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PANCREATOLOGY
·
2023
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IF 3.6
Xin Wu,Xin Zhang,Peng Liu,Yao Wang
Background Pancreatic cancer is a common digestive system cancer and one of the most lethal malignancies worldwide. Ataxin-3 (ATXN3) protein is a deubiquitinating enzyme implicated in the occurrence of diverse human cancers. The potential role of ATXN3 in pancreatic cancer still remains unclear. Methods ATXN3 was screened from differentially-upregulated genes of GSE71989, GSE27890 and GSE40098 datasets. The mRNA and protein levels of ATXN3 was evaluated in pancreatic cancer samples and cell lines. Through the gain- and loss-of-function experiments, the effects of ATXN3 on cell proliferation , migration and invasion were evaluated using cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) staining, wound healing and Transwell assays. Subsequently, the interaction between ATXN3 and HDAC6 was confirmed using double immunofluorescence staining, co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The underlying mechanism of ATXN3 was determined by knockdown of HDAC6 in ATXN3-upregulated pancreatic cancer cells. The function of ATXN3 in vivo was verified through xenograft assay. Results High expression of ATXN3 was found in pancreatic cancer tissues. Increased ATXN3 expression dramatically promoted cell proliferation, migration, and invasion. The malignant phenotypes were suppressed in ATXN3-silenced pancreatic cancer cells. ATXN3 was proved to interact with HDAC6 and regulate its degradation through deubiquitination . Downregulation of HDAC6 inhibited ATXN3-induced development of pancreatic cancer cells through regulating the expression of PCNA, vimentin and E-cadherin. ATXN3 facilitated tumor growth of pancreatic cancer and increased HDAC6 expression in vivo . Conclusions This study confirmed that ATXN3 facilitated malignant phenotypes of pancreatic cancer via reducing the ubiquitination of HDAC6.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·Vol. 69
·期 15
·17995-18024
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IF 7.3
Lu Daoran,Liu Rongfeng,Zheng Congcong,Sun Yueyi,Gao Jianjun,Luan Yepeng
Targeted
protein degradation via hydrophobic tagging technology
presents a promising strategy for modulating disease relevant proteins.
As a unique member of the histone deacetylase (HDAC) family, HDAC6
is involved in inflammatory pathways and is a potential therapeutic
target for inflammatory diseases. Herein, we report a group of novel
hydrophobic tag based HDAC6 degraders by modifying the structure of
Nexturastat A and identified 20c as a lead compound which
selectively degrades HDAC6 in vitro (half-degradation concentration
= 1.1 μM) in a ubiquitin-proteasome system dependent manner
without obviously impacting six other HDAC isoforms. In a dextran
sulfate sodium (DSS)-induced colitis model, 20c alleviated
disease symptoms, reduced colon shortening, and downregulated pro-inflammatory
cytokines. Transcriptomic and biochemical analyses revealed that 20c suppresses NF-κB signaling through the HDAC6–HSP90–NF-κB
axis. Overall, this work validated the potential of hydrophobic tag
based HDAC6 degrader as therapeutic means for ulcerative colitis.
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JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Lin Yu,Lu Zhang,Lulu Gao,Siyue Huang,Xueying Qin,Zirui Wang,Siqi Li,Chunyan Mei,Maolin Zhang,Yaojing Zhang,Wei Wang,Min Wu,Jingjing Liu
Liver fibrosis is a common outcome of chronic liver injury and can progress to cirrhosis, yet effective anti-fibrotic therapies remain limited. Here, we identify histone deacetylase 6 (HDAC6) as the most consistently upregulated zinc-dependent HDAC in fibrotic livers and activated hepatic stellate cells (HSCs). However, systemic HDAC6 inhibition may be constrained by inefficient delivery to fibrogenic HSCs and increased off-target exposure. To enable selective HDAC6 inhibition in activated HSCs, we developed an activated HSC membrane-camouflaged PLGA nanomedicine (PLGA-Ric@HSCM) loaded with the HDAC6 inhibitor ricolinostat (Ric). Membrane cloaking preserves key adhesion and recognition proteins, promotes homotypic uptake by HSCs, and reduces macrophage sequestration in vivo . PLGA-Ric@HSCM dampened profibrotic transcriptional programs by restoring microtubule acetylation and suppressing both the canonical TGFβ/Smad2/3 pathway and the p38/c-JUN/ATF2 axis. Compared to PLGA-Ric, PLGA-Ric@HSCM shows a more pronounced reduction in fibrosis burden and improved hepatic pathology across etiologically distinct models. Together, PLGA-Ric@HSCM provides a biomimetic, HSC-targeted strategy to reprogram acetylation homeostasis via HDAC6 inhibition and consequently mitigate liver fibrogenesis.
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iScience
·
2024
·
IF 4.6
Yixiao Li,Yuhan Jiang,Haoyi Yan,Ziheng Qin,Yidi Peng,Danyu Lv,Hongquan Zhang
Histone lysine isonicotinylation (Kinic) induced by isoniazid (INH) was recently identified as a post-translational modification in cells. However, global cellular non-histone proteins Kinic remains unclear. Using proteomic technology, we identified 11,442 Kinic sites across 2,792 proteins and demonstrated that Kinic of non-histone proteins is involved in multiple function pathways. Non-histone proteins Kinic can be regulated by isonicotinyl-transferases, including CBP and Tip60, and deisonicotinylases, including HDAC8 and HDAC6. In particular, the Kinic of poly (ADP-ribose) (PAR) polymerase 1 (PARP1) can be catalyzed by CBP and deisonicotinylation can be catalyzed by HDAC8. Tip60 and HDAC6 are isonicotinyl-transferase and the deisonicotinylase of SMAD3, respectively. Importantly, we found the K378inic of SMAD3 increases its phosphorylation, activates TGFβ pathway, and promotes liver cancer cells migration and invasion. In conclusion, our study demonstrated non-histone proteins Kinic occur extensively in cells and plays an important role in regulation of various cellular functions, including cancer progression.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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蛋白质组学
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Lin Yu,Lulu Gao,Bing Liang,Lu Zhang,Min Wu,Jingjing Liu
While sonodynamic therapy (SDT) has shown promise in treating triple-negative breast cancer (TNBC) due to its non-invasive nature, deep tissue penetration, and induction of immunogenic cell death (ICD), its efficacy remains limited by the complex immunosuppressive tumor microenvironment (TME). In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric). GdNPs/Ce6-Ric effectively accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and release Ce6 and Ric in response to the acidic TME. Upon ultrasound stimulation, GdNPs/Ce6-Ric induce cancer cell apoptosis and trigger ICD by generating reactive oxygen species (ROS), which activate cytotoxic T cells and promote tumor cell elimination. Notably, the epigenetic modulation by Ric within the immunosuppressive TME increased the proportion of natural killer (NK) cells and cytotoxic T cells while decreasing the population of immunosuppressive regulatory T (Treg) cells. This modulation synergistically enhanced the anti-tumor effects of SDT by downregulating the HDAC6/p-STAT3/PD-L1 pathway. Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC.
研究领域:
肿瘤学
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医学
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生物化学
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免疫学
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CELL BIOLOGY AND TOXICOLOGY
·
2022
·
IF 6.819
Pang Xuefeng,Guan Qigang,Lin Xue,Chang Ning
Histone deacetylases (HDACs) has been implicated in cardiac diseases, while the role of HDAC6 in dilated cardiomyopathy (DCM) remains obscure. The in silico analyses predicted potential association of HDAC6 with autophagy-related genes and DCM. Thus, we evaluated the functional relevance of HDAC6 in DCM in vivo and in vitro. We developed a rat model in vivo and a cell model in vitro by doxorubicin (DOX) induction to simulate DCM. HDAC6 expression was determined in myocardial tissues of DCM rats. DCM rats exhibited elevated HDAC6 mRNA and protein expression as compared to sham-operated rats. We knocked HDAC6 down and/or overexpressed NLRP3 in vivo and in vitro to characterize their roles in cardiomyocyte autophagy. It was established that shRNA-mediated HDAC6 silencing augmented cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation, thus ameliorating cardiac injury in myocardial tissues of DCM rats. Besides, in DOX-injured cardiomyocytes, HDAC6 silencing also diminished NLRP3 inflammasome activation and cell apoptosis but enhanced cell autophagy, whereas ectopic NLRP3 expression negated the effects of HDAC6 silencing. Since HDAC6 knockdown correlates with enhanced cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation through an interplay with NLRP3, it is expected to be a potential biomarker and therapeutic target for DCM. Graphical abstract 1. HDAC6 was up-regulated in DCM rats. 2. HDAC6 knockdown promoted cardiomyocyte autophagy to relieve cardiac dysfunction. 3. HDAC6 knockdown inhibited NLRP3 inflammasome and promoted cardiomyocyte autophagy. 4. Silencing HDAC6 promoted autophagy and repressed apoptosis in cardiomyocytes. 5. This study provides novel therapeutic targets for DCM.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Mengqi Li,Yu Wang,Xinru Liang,Congke Zhao,Wenhua Tan,Ruizhe Gao,Yuanbo Hu,Sufang Xiang,Zhuo Chen,Liqing Hu,Qianbin Li
Recent studies suggested that disrupting the Hsp110-STAT3 interaction is a promising strategy for treating pulmonary arterial hypertension (PAH). However, the restricted reduction in p-STAT3 required to prevent vascular remodeling limits Hsp110-STAT3 PPI inhibitor development. Our preliminary studies revealed that HDAC6 activation in HPAECs contributes to p-STAT3 upregulation. Subsequently, a series of Hsp110/HDAC6 dual-target inhibitors were rationally designed and synthesized. Structure–activity relationship studies identified 15n as a potent dual-target inhibitor, effectively interrupting the Hsp110-STAT3 interaction and suppressing HDAC6 activity. In vitro, 15n exhibited a synergistic effect in suppressing the STAT3 signaling pathway by concurrently targeting Hsp110 and HDAC6, thereby inhibiting the abnormal proliferation and migration of the HPAECs. In vivo, compared with combination therapy, 15n demonstrated enhanced suppressive effects on vascular remodeling through synchronous regulation of dual targets. In summary, the present study provides novel research insights into developing novel PAH drugs based on antivascular remodeling strategies and offers a promising lead compound.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Jiang Mingzhou,Zhu Zhidong,Zhou Ziyu,Yan Zhiqiang,Huang Kai,Jiang Rongrong,Fan Xi,Jieensi Milayi,Pang Liewen,Wang Yiqing,Sun Xiaotian
Background Cardiovascular events secondary to stroke–collectively classified as stroke-heart syndrome–greatly impair the patient’s prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model.Results The specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment.Conclusion This study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection.Graphical Abstract
研究领域:
神经科学
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心血管疾病
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药物递送系统
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炎症
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分子生物学
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高影响因子
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