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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PubMed
高影响因子
Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-15
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IF 9.6
Cen Junjie,Zhao Dongliang,Shi Xin,Chen Jinlong,Zhou Hang,Liang Yanping,Gui Chengpeng,Chen Wei,Luo Junhang,Chen Xu
Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
研究领域:
分子生物学
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癌症研究
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生物化学
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细胞生物学
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转化医学
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Cell Death & Disease
·
2024
·Vol. 15
·期 12
·1-14
·
IF 8.1
Chen Li,Zou Yahui,Sun Renhong,Huang Mei,Zhu Xiaotong,Tang Xiao,Yang Xiaobao,Li Dake,Fan Gaofeng,Wang Yu
Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 6.7
Mingzhu Zhang,Ke Wang,Guoli Li,Xinlu Bao,Kebin Ye,Aoyun Cui,Jishuang Zhang,Lin Zhou
Photodegradation-targeting chimeras (PDTACs) addresses the off-target toxicity issues of proteolysis-targeting chimeras (PROTACs) in terms of technical principle; Difficulty in defining tumor boundaries and controlling light exposure increases the risk of damaging peritumoral tissues if light exposure oversteps the tumor. This study discovered that compared to SV-HUC-1 cells (normal cells), Von Hippel-Lindau (VHL) exhibits more active regulation of CDK2/4 in T24 cells (bladder cancer cells); Based on this, a series of PDTACs linking VHL ligands to photosensitizers were synthesized, and ZnPc-PEG 2 -VH032 was selected as the most potent antitumor compound. This compound degrades VHL upon light exposure and, when combined with photodynamic therapy (PDT), efficiently kills T24 cells with a phototoxicity index (PI) of 36,397. More importantly, after illumination, ZnPc-PEG 2 -VH032 exhibited a selectivity index (SI) of 749 for killing T24 cells versus SV-HUC-1 cells, achieving selective tumor cell targeting under light conditions and effectively mitigating the risk of damage to peritumoral tissues. This study demonstrates the potential of VHL as a precision therapeutic target for tumors and identifies the first PDTAC drug characterized by high PI and SI. It provides novel insights and structural references for developing drugs that selectively kill tumor cells.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 7.088
Xing-Rong Wang,Shuai Wang,Hong-Xia Mu,Kai-Yan Xu,Xue-Ting Wang,Jian-Tao Shi,Qi-Hang Cui,Li-Wen Zhang,Shi-Wu Chen
VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro , as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC 50 : 0.084 ± 0.04 μM, D max : 73.7%) and HUVEC cells (DC 50 : 0.51 ± 0.10 μM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G 2 /M phase cycle arrest and apoptosis . All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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高影响因子
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