Modulating G6PD/PGD to overcome FSP1/DHODH-mediated ferroptosis defence: A novel oridonin derivative suppresses liver cancer
文献类型：期刊论文
| 作者 | Ma, Chenhui4,5,6; Han, Li4,5; Yao, Hong3; Zhao, Wenxuan2; Chen, Feihong4,5; Wu, Xiuyuan3; Li, Guoqi2; Huang, Ruimin2,4,5; Pang, Cheng Heng6; Zhu, Zheying1 |
| 刊名 | BRITISH JOURNAL OF PHARMACOLOGY
 |
| 出版日期 | 2025-08-27 |
| 页码 | 19 |
| 关键词 | ferroptosis FSP1 and DHODH G6PD and PGD liver cancer oridonin |
| ISSN号 | 0007-1188 |
| DOI | 10.1111/bph.70160 |
| 通讯作者 | Pang, Cheng Heng(chengheng.pang@nottingham.edu.cn) ; Zhu, Zheying(zheying.zhu@nottingham.ac.uk) ; Xu, Jinyi(jinyixu@china.com) ; Pan, Guoyu(gypan@simm.ac.cn) |
| 英文摘要 | Background Hepatocellular carcinoma (HCC), a globally prevalent malignancy with high mortality rates, presents an unmet need for innovative effective therapies.Purpose This study aimed to explore the antitumour potential of compound XD, a novel oridonin derivative, on HCC and its underlying mechanism.Experimental Approach The antitumour effects of compound XD were investigated in several HCC cells lines and mice models. The mechanism of XD was investigated using FACS, qPCR, WB, ELISA, IHC, siRNA and plasmid transfection.Key Results Compound XD demonstrated potent inhibitory effects, surpassing sorafenib with a maximum of 10-fold lower IC50 values against HCC cell lines. Its anticancer activities were ferroptosis dependent, which could be attenuated by ferroptosis inhibitors including deferoxamine, ferrostatin-1 and N-acetyl-cysteine. Unlike sorafenib, XD decreased two pivotal regulator FSP1 and DHODH to induce ferroptosis, while their overexpression partially mitigated XD-induced cytotoxicity and lipid peroxidation. In addition, XD treatment decreased cellular NADPH levels and inhibited the expression of G6PD and PGD in NADPH generation. Overexpression of G6PD or PGD reversed FSP1 and DHODH down-regulation, rescuing the ferroptosis induced by XD. Bioinformation analysis indicated the significant up-regulation of G6PD and PGD in clinical HCC patients and was positively correlated with cancer stages. Molecular docking and CETSA assay confirmed the binding capacity of XD with G6PD and PGD protein. Finally, XD dose-dependently inhibited liver tumour growth and induced ferroptosis-related markers in mice.Conclusion and Implications This study suggests XD as a potential ferroptosis inducer and the potential role of G6PD/PGD/FSP1/DHODH axis in governing ferroptosis sensitivity in HCC. |
| WOS关键词 | BIOLOGICAL EVALUATION ; GUIDE |
| 资助项目 | University of Nottingham Ningbo China |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001557055000001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321348]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Pang, Cheng Heng; Zhu, Zheying; Xu, Jinyi; Pan, Guoyu |
| 作者单位 | 1.Univ Nottingham, Sch Pharm, Div Mol Therapeut & Formulat, Univ Pk Campus, Nottingham, England 2.Nanjing Univ Chinese Med, Nanjing, Peoples R China 3.China Pharmaceut Univ, Dept Med Chem, State Key Lab Nat Med, Nanjing, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Haike Rd 501, Shanghai, Peoples R China 6.Univ Nottingham Ningbo China, Dept Chem & Environm Engn, Ningbo, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Chenhui,Han, Li,Yao, Hong,et al. Modulating G6PD/PGD to overcome FSP1/DHODH-mediated ferroptosis defence: A novel oridonin derivative suppresses liver cancer[J]. BRITISH JOURNAL OF PHARMACOLOGY,2025:19. |
| APA | Ma, Chenhui.,Han, Li.,Yao, Hong.,Zhao, Wenxuan.,Chen, Feihong.,...&Pan, Guoyu.(2025).Modulating G6PD/PGD to overcome FSP1/DHODH-mediated ferroptosis defence: A novel oridonin derivative suppresses liver cancer.BRITISH JOURNAL OF PHARMACOLOGY,19. |
| MLA | Ma, Chenhui,et al."Modulating G6PD/PGD to overcome FSP1/DHODH-mediated ferroptosis defence: A novel oridonin derivative suppresses liver cancer".BRITISH JOURNAL OF PHARMACOLOGY (2025):19. |
入库方式： OAI收割
来源：上海药物研究所
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