INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2025
·Vol. 26
·期 1
·312
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IF 4.9
Rui Zhang,Siyuan Peng,Xuejuan Zhang,Zhengwei Huang,Xin Pan
Objective: The objective of this study was to explore the possibility of treating heart failure in rats by delivering mRNA of 24-dehydrocholesterol reductase (DHCR24) into the body through lipid nanoparticles (LNPs). Methods: We established a heart failure rat model using doxorubicin. The experiment was divided into blank, model, mRNA stock solution cardiac injection, mRNA stock solution intravenous injection, LNP-mRNA stock solution cardiac injection, and LNP-mRNA stock solution intravenous injection groups. We directly injected DHCR24-mRNA or LNP-DHCR24-mRNA into the myocardium in three regions through an insulin needle passing through the intercostal space under the guidance of B-ultrasound. We recorded the mortality rate, body weight, 6-min walk test return times, and organ weight of rats after administration and detected the cardiac structure and function using B-ultrasound and transmission electron microscopy (TEM). Additionally, we tested for HE staining; PRDX2, Sirt3, and TRX1 protein expression; and IL-1 β, IL-10, VEGF, NT proBNP, and BNP cytokine concentrations. Results: Compared with the model group, the administration of DHCR24-mRNA significantly reduced mortality; decreased weight loss, the ratio of heart to tibia length, and spleen weight; and improved rat motility. The administration of DHCR24-mRNA can postpone the pathological morphological alterations of myocardial cells and reduce inflammatory infiltration. In terms of biochemistry, the administration of DHCR24-mRNA can increase the expression of the PRDX2, Sirt3, and TRX1 proteins; increase the concentrations of IL-10 and VEGF; and reduce the concentrations of IL-1β, NT proBNP, and BNP. The administration of DHCR24-mRNA can also delay the process of heart failure. The delivery and therapeutic effect of DHCR24-mRNA encapsulated in LNPs were better when compared to the other groups. Conclusions: DHCR24-mRNA encapsulated in LNPs can be effectively administered to rats with heart failure and exhibits some curative effects.
研究领域:
心血管病学
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分子生物学
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药理学
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Cell Reports
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2025
·Vol. 44
·期 12
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IF 6.9
Yunfei Zhou,Xinxin Yang,Jianwen Xu,Yidi Wu,Yin Fu,Yihong Dong,Xun Yang,Qiang Fu,Chenxu Guo,Yunjing Hou,Shuyuan Chang,Jun Yan,Ju Ran,Yumeng Wang,Qingxin Zhang,Tomii Ayaka,Lei Yu,Feng Geng,Liuyang Zhao,Xiaoyang Hu,Shuijie Li,Hongxue Meng,Dabin Liu
Dysregulated cholesterol synthesis fuels cancer progression, but its precise role in hepatocellular carcinoma (HCC) remains unclear. Here, we identify elevated acetylation of 24-dehydrocholesterol reductase (DHCR24) at Lys254 as a hallmark of HCC. Both total DHCR24 and its K254 acetylation independently predict poor patient survival. Acetylation stabilizes DHCR24, sustaining hepatic cholesterol synthesis and promoting tumorigenesis. Mechanistically, DHCR24 acetylation enhances 7-ketocholesterol accumulation, which upregulates p62 and drives HCC growth in vitro and in vivo . Pharmacologic inhibition of DHCR24 expression and acetylation with the US Food and Drug Administration (FDA)-approved drug irbesartan suppresses cell proliferation and reduces tumor burden in xenograft and carcinogen-induced mouse models. Reduced p62 expression parallels the antitumor effects. These findings define DHCR24 acetylation as a metabolic switch linking sterol synthesis to oncogenesis and highlight the DHCR24-7-ketocholesterol-p62 axis as a therapeutic target for HCC.
研究领域:
癌症生物学
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分子肿瘤学
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代谢调控
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肝脏病学
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转化医学
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METABOLIC BRAIN DISEASE
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2026
·Vol. 41
·期 1
·153
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IF 3.8
Li Chunlei,Li Yuan,Liu Tongyan,Zong Yue,Zhou Lingyun
Spinal cord injury (SCI) is a highly disabling condition affecting the central nervous system (CNS). Neuroinflammation and neuronal apoptosis are two critical factors in the pathological process of SCI. Although electroacupuncture (EA) has been reported to alleviate neuroinflammation in brain injury, the underlying molecular mechanism remains unclear. Transcriptome sequencing of spinal cord tissues was performed to identify potential key factors and pathways involved in EA post-SCI. DHCR24, a cholesterol synthesis regulator, was selected as a key candidate and DHCR24 was downregulated after SCI (log 2 FC = -1.6, P < 0.01), and this downregulation was notably reversed by EA treatment (log 2 FC = 1.04, P < 0.01). We investigated the neuroprotective effect of DHCR24 against neuron death and neuroinflammation in SCI, with a particular focus on its effects on the Wnt signaling pathway. SCI-induced DHCR24 downregulation was associated with decreased expression of the axonal regeneration marker NF and increased activation of Iba1/CCR7-positive microglia, accompanied by enhanced neuronal apoptosis and inflammatory factor release. Importantly, functional validation experiments demonstrated that DHCR24 was required for the therapeutic effects of EA. Complementary in vitro studies in LPS/IFN-γ-stimulated BV2 microglia cells confirmed the role of DHCR24 in microglial polarization and neuronal survival, likely via Wnt signaling activation. Integrating transcriptomic and mechanistic evidence, we demonstrate that DHCR2 promotes Wnt pathway activation, reduces neuronal apoptosis and neuroinflammation, and ultimately enhances spinal cord repair. This study provides evidence supporting the potential clinical application of EA in SCI recovery and identifies DHCR24 may be a key mechanistic target underlying its therapeutic effects. Graphical
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Frontiers in Aging Neuroscience
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2022
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IF 5.702
Yang Xiao-bo,Zu Heng-bing,Zhao Yong-fei,Yao Kai
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.
研究领域:
神经科学
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药理学
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神经退行性疾病
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International Journal of Biological Sciences
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2026
·Vol. 22
·期 7
·3886-3908
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IF 11.7
Cai Yuchen,Zhou Tianyi,Sun Jiaming,Cai Xueyao,Shi Wenjun,Chen Junzhao,Zouboulis Christos C.,Sun Hao,Fu Yao,Chen Liangbo
Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (ARMGD) is highly prevalent but mechanistically unclear, leading to significant visual impairment without targeted therapies. To identify key molecular drivers of ARMGD, we performed integrated multi-omics screening of aging mouse meibomian glands (MGs) and identified DHCR24, a key cholesterol metabolism enzyme, as a critical regulator of gland homeostasis. Single-cell sequencing identified age-associated downregulation of Dhcr24 predominantly in meibocytes. Based on this finding, we generated a meibocyte-specific Dhcr24 knockout (cKO) model, which exhibited typical ARMGD pathology including glandular atrophy, disrupted lipid homeostasis, and inflammatory activation. Further in vitro studies using SZ95 sebocytes demonstrated that DHCR24 deficiency induces mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, triggering cGAS/STING-dependent inflammatory senescence. Notably, AAV-mediated restoration of DHCR24 in mice reversed age-related gland pathology. Our findings establish DHCR24 as a dual-target regulator that maintains cholesterol metabolic homeostasis while suppressing mtDNA-driven inflammation via the cGAS-STING pathway, highlighting its therapeutic potential for ARMGD and related disorders characterized by lipid-inflammatory imbalance.
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