Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-16
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IF 9.6
Yang Mengxue,Wang Ting,Shao Jingrong,Ran Xinna,Xiao Rui,Zhao Rui,Wu Chunyan,Ji Ming,Tian Weiping,Sun Huabing,Liu Jiao,Zuo Shengkai
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
研究领域:
心脏病学
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分子生物学
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药理学
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细胞死亡
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Jiao Xue,Yining Zhu,Shuting Bai,Chunting He,Guangsheng Du,Yuandong Zhang,Yao Zhong,Wenfei Chen,Hairui Wang,Xun Sun
Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles ( [email protected] ), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of [email protected] was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that [email protected] could serve as an innovative and effective strategy for combined cancer therapy.
研究领域:
癌症治疗
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纳米技术
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免疫学
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材料科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Shunzhe Zheng,Meng Li,Wenqian Xu,Jiaxin Zhang,Guanting Li,Hongying Xiao,Xinying Liu,Jianbin Shi,Fengli Xia,Chutong Tian,Ken-ichiro Kamei
The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.
研究领域:
癌症研究
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药学
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纳米技术
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2022
·
IF 15.304
Wenfei Chen,Chunting He,Nan Qiao,Zhaofei Guo,Shilong Hu,Yuanshuai Song,Hairui Wang,Zhirong Zhang,Bowen Ke,Xun Sun
Intratumoral environment as a hypoxic, non-inflamed “cold” state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS–N782 and JQ-1 derivatives to obtain the biohybrid agent N –V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS–N782, N –V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed “hot” tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy .
研究领域:
癌症生物学
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免疫学
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治疗学
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DOI
PubMed
高影响因子
Materials Today
·
2023
·
IF 24.2
Xiao-Kang Jin,Jun-Long Liang,Shi-Man Zhang,Qian-Xiao Huang,Shun-Kang Zhang,Chuan-Jun Liu,Xian-Zheng Zhang
Owing to the deficiency of infiltrating immune cells and the accumulation of immunosuppressive cells in tumor microenvironment (TME), immunotherapy remains enormous challenges in colorectal cancer (CRC). Here, CRC was found to be sensitive to cuproptosis which could further evoke immune responses and mediate immune resistance. Thus, a cuproptosis-mediated immunotherapy nanoreactor (CCJD-FA) was constructed by encapsulating copper-based shell-coated CaO 2 and bromodomain-containing protein 4 inhibitor JQ-1 with DSPE-PEG-FA. Within tumor cells, CCJD-FA was disassembled under GSH environment, and the exposed CaO 2 could generate H 2 O 2 under the acidic condition, which reacted with the released Cu 2+ via Fenton-like reaction to produce O 2 for relieving hypoxia and Cu + for inducing cuproptosis. Furthermore, CCJD-FA could also inhibit intracellular glycolysis and ATP generation, then blocking the Cu + efflux protein ATP7B. Meanwhile, the IFN-γ-induced PD-L1 expression could be exactly reduced by the BRD4 suppression and oxygen supply. These effects sensitized cancer cells to cuproptosis, further evoking systemic immune responses and reshaping immunosuppressive TME to inhibit tumor growth.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
✓ 已验证
产品关联
DOI
高影响因子
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