Animals
·
2023
·Vol. 13
·期 24
·3832
·
IF 3
Hongmei Xu,Yueyue Li,Qiao Li,Zifeng Ma,Shi Yin,Honghong He,Yan Xiong,Xianrong Xiong,Daoliang Lan,Jian Li,Wei Fu
Simple SummaryIn recent years, authoritative journals have consistently reported DHODH’s critical role in resistance to ferroptosis, significantly advancing the research on related mechanisms. Nevertheless, the nucleotide sequence of the yakDHODHgene remains unknown, and its involvements in ferroptosis processes in yak cells remain elusive. Therefore, in the present study, we cloned the coding region of the yakDHODHgene, and revealed its high conservation in mammals. Furthermore, by using a bisphenol S (BPS)-induced ferroptosis model, we confirmed the role of theDHODHgene in mitigating ferroptosis in yak skin fibroblasts (YSFs) derived from a three-mouth-old fetus. This study offers theoretical support for further exploring the functions of the yakDHODHgene and partially elucidating the molecular mechanisms underlying ferroptosis.AbstractDihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme ofde novobiosynthesis of pyrimidine. Although the involvement of DHODH in resisting ferroptosis has been successively reported in recent years, which greatly advanced the understanding of the mechanism of programmed cell death (PCD), the genetic sequence of the yakDHODHgene and its roles in ferroptosis are still unknown. For this purpose, we firstly cloned the coding region sequence ofDHODH(1188 bp) from yak liver and conducted a characterization analysis of its predictive protein that consists of 395 amino acids. We found that the coding region of the yakDHODHgene presented high conservation among species. Second, the expression profile of theDHODHgene in various yak tissues was investigated using RT-qPCR. The results demonstrated thatDHODHwas widely expressed in different yak tissues, with particularly high levels in the spleen, heart, and liver. Third, to investigate the involvement ofDHODHin regulating ferroptosis in cells, yak skin fibroblasts (YSFs) were isolated from fetuses. And then, bisphenol S (BPS) was used to induce thein vitroferroptosis model of YSFs. We observed that BPS decreased the cell viability (CCK8) and membrane potential (JC-1) of YSFs in a dose-dependent manner and induced oxidative stress by elevating reactive oxygen species (ROS). Simultaneously, it was evident that BPS effectively augmented the indicators associated with ferroptosis (MDA and BODIPY staining) and reduced GSH levels. Importantly, the co-administration of Ferrostatin-1 (Fer), a potent inhibitor of ferroptosis, significantly alleviated the aforementioned markers, thereby confirming the successful induction of ferroptosis in YSFs by BPS. Finally, overexpression plasmids and siRNAs of the yakDHODHgene were designed and transfected respectively into BPS-cultured YSFs to modulateDHODHexpression. The findings revealed thatDHODHoverexpression alleviated the occurrence of BPS-induced ferroptosis, while interference ofDHODHintensified the ferroptosis process in YSFs. In summary, we successfully cloned the coding region of the yakDHODHgene, demonstrating its remarkable conservation across species. Moreover, using BPS-induced ferroptosis in YSFs as the model, the study confirmed the role of theDHODHgene in resisting ferroptosis in yaks. These results offer valuable theoretical foundations for future investigations into the functionality of the yakDHODHgene and the underlying mechanisms of ferroptosis in this species.Keywords:yak;DHODHgene;fetal fibroblasts;ferroptosis;Bisphenol S
研究领域:
分子生物学
·
细胞生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Qiang Zhang,Kaisa Cui,Yue Kong,Jing Yu,Zhanhao Luo,Xiaoya Yang,Liang Gong,Yanchun Xie,Jiuxiu Lin,Chen Liu,Zongjin Zhang,Yugeng Liu,Bingxin Liu,Dayi Liang,Wanyi Zeng,Zhen He,Ping Lan
c-Myc (Myc)-driven cancers exhibit aggressive phenotypes and therapeutic resistance. Here, integrating CRISPR-Cas9 screening, we identify dihydroorotate dehydrogenase (DHODH) as a promising target in Myc-driven cancer. Mechanistically, DHODH interacts with Myc to stabilize it independently of its enzymatic activity, thereby antagonizing SKP2-mediated polyubiquitination and proteasomal degradation. EN4, a Myc transcriptional activity inhibitor, disrupts DHODH-Myc interaction, promoting Myc degradation via SKP2. Additionally, Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense, processes dependent on DHODH enzymatic activity. Clinically, DHODH positively correlates with Myc, activating pyrimidine metabolism and ferroptosis defense in Myc-driven cancers. Hyperactivation of the DHODH-Myc axis is linked to colorectal cancer progression and poor prognosis. Therapeutically, combining EN4 with a DHODH enzymatic inhibitor demonstrates potent antitumor efficacy in Myc-driven colorectal cancer. Overall, our findings elucidate the metabolic and non-metabolic roles of DHODH in Myc-driven cancer, underscoring its dual potential as a therapeutic target addressing both enzymatic and non-enzymatic functions.
研究领域:
肿瘤学
·
分子生物学
·
癌症遗传学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2026
·
IF 16.6
Zhao Yuheng,Ou Chunxian,Huang Huimin,Wang Yujue,Shen Jiaxi,Li Yaoyi,He Qingmei,Han Zeteng,Xie Yuer,Zhong Tianyun,Xu Sha,Liu Na,Wang Gao-Yuan,Ma Jun,Li Yingqin
Metabolic reprogramming under therapeutic stress may represent a targetable vulnerability for cancer treatment. Elucidation of the metabolic alterations linked to chemotherapy in nasopharyngeal carcinoma (NPC) could uncover potential therapeutic strategies. Using proteomics and transcriptomic profiles, we identified wild-type IDH1 as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin chemotherapy (GP)-resistant NPC. IDH1 reprogrammed nucleotide metabolism in response to chemotherapy, linking DNA damage repair (DDR) to ferroptosis resistance via DHODH, thereby contributing to chemoresistance in NPC. Mechanistically, α-ketoglutarate (α-KG), a metabolite of IDH1, enhanced chromatin accessibility to promote DHODH transcription via α-KG-dependent dioxygenase ALKBH5-recruited HNRNPC. The DHODH inhibitor BAY2402234 markedly sensitized NPC cells to chemotherapy. Clinically, a prognostic model based on DDR and ferroptosis signatures effectively predicted disease relapse risk post-chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/α-KG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring wild-type IDH1.
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 12
·2607
·
IF 4.6
Kaige Li,Wei Xia,John Z. H. Zhang
To address the surge inAspergillus fumigatusinfections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional structure of AfDHODH was constructed via homology modeling. Molecular docking, dynamics simulations, and binding free energy calculations systematically elucidated the mechanisms of existing inhibitors. Virtual screening against the ZINC20 and ChEMBL databases yielded 13 candidates, with two micromolar inhibitors (IC50< 100 μM) identified through in vitro assays. These inhibitors exhibited novel scaffold structures that were distinct from known DHODH inhibitors. The results validate the feasibility of homology modeling-guided antifungal discovery and these findings provide critical insights for the development of new antifungal agents.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Shanlong Zhang,Li Kang,Xiaoxue Dai,Junlan Chen,Zhengtao Chen,Meixiang Wang,Huantong Jiang,Xin Wang,Suqin Bu,Xinyuan Liu,Guohui Zhang,Hua Tang
Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl 2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl 2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS–STING signaling pathway. When inhibiting the cGAS–STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl 2 -induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl 2 . Mechanistically, these results revealed that Manganese treatment-activated cGAS–STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.
研究领域:
癌症生物学
·
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Jie Shen,Zhongkai Wu,Yu Zhou,Dashuai Yang,Xin Wang,Bin Yu,Kailiang Zhao,Youming Ding
SLC16A3/monocarboxylate transporter 4 (MCT4) regulates intracellular lactate transport and is highly expressed in many tumors, indicating poor prognosis. It may be related to inducing hypoxia, apoptosis and other mechanisms, but the study of MCT4 in HCC is far from complete. In this study, we first analyzed the expression of SLC16A3 in HCC tumor and non-tumor tissue samples based on TCGA data and immunohistochemistry. Subsequently, the effects of SLC16A3 expression on cell proliferation and invasion were analyzed using hepatocellular carcinoma (HCC) lines, and Western blot (WB) analysis was performed to explore the changes in pathway proteins and ferroptosis proteins. Finally, the drug sensitivity was tested by CCK8 kit. We found that SLC16A3 was significantly upregulated in tumor tissues, and was significantly correlated with TNM stage, histological grade, and macrovascular invasion. TCGA data and WB analysis showed that the high expression of SLC16A3 induced hypoxia, and knockdown could reverse hypoxia and inhibit ERK phosphorylation, thus limiting the malignant behavior of HCC cells. Moreover, knockdown of SLC16A3 significantly increased the level of lipid peroxidation and reactive oxygen species (ROS), while the expressions of GPX4, DHODH and SLC7A11 were inhibited. The expression of SLC16A3 affected the sensitivity of HCC cells to chemotherapy and targeted drugs, and RNA sequencing data suggested that the expression level influenced tumor microenvironment and response to immunotherapy. So, we draw a conclude that SLC16A3 is associated with poor prognosis of HCC. Inhibition of SLC16A3 expression is a potential therapeutic target for HCC.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Panpan Xue,Huilan Zhuang,Sijie Shao,Tingjie Bai,Xuemei Zeng,Shuangqian Yan
The activation of cellular ferroptosis is promising in tumor therapy. However, ferroptosis is parallelly inhibited by antiferroptotic substances, including glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1). Thus, it is highly desirable, yet challenging, to simultaneously suppress these three antiferroptotic substances for activating ferroptosis. Here, we rationally designed a hollow iron-doped SiO2-based nanozyme (FeSHS) loaded with brequinar (BQR) and lificiguat (YC-1), named FeSHS/BQR/YC-1-PEG, for tumor ferroptosis activation. FeSHS were developed through the continuous etching of SiO2 nanoparticles by iron ions, which exhibit pH/glutathione-responsive biodegradability, along with mimicking the activities of peroxidase, glutathione oxidase, and NAD(P)H oxidase. Specifically, glutathione depletion and NAD(P)H oxidation by FeSHS will suppress the expression of GPX4 and inhibit FSP1 by disrupting the NAD(P)H/FSP1/ubiquinone axis. In addition, the released BQR can suppress the expression of DHODH. Meanwhile, YC-1 is able to increase the cellular polyunsaturated fatty acids (PUFAs) by destroying the HIF-1α/lipid droplet axis. The elevation of levels of iron and PUFAs while simultaneously disrupting the GPX4/DHODH/FSP1 inhibitory pathways by our designed nanoplatform displayed high therapeutic efficacy both in vitro and in vivo. This work elucidates rationally designing smart nanoplatforms for ferroptosis activation and future tumor treatments.
研究领域:
纳米技术
·
癌症治疗
·
生物化学
·
材料科学
·
生物医学工程
✓ 已验证
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）