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| 1 | Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2显示文摘Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not. | Rui Xiong Leike Zhang Shiliang Li Yuan Sun Minyi Ding Yong Wang Yongliang Zhao Yan Wu Weijuan Shang Xiaming Jiang Jiwei Shan Zihao Shen Yi Tong Liuxin Xu Yu Chen Yingle Liu Gang Zou Dimitri Lavillete Zhenjiang Zhao Rui Wang Lili Zhu Gengfu Xiao Ke Lan Honglin Li Ke Xu | 2020 | Protein & Cell2020，11，10： | 14 |
| 2 | CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma:a cross-talk between FGF21 and the NRF2 pathway显示文摘The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance. | Jiang Chen Shi Jiang Huijiang Shao Bixia Li Tong Ji Daniel Staiculescu Jiayan He Jie Zhao Liuxin Cai Xiao Liang Junjie Xu Xiujun Cai | 2022 | Science China(Life Sciences)2022，65，10： | 4 |
| 3 | Correction to:Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2显示文摘CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/. | Rui Xiong Leike Zhang Shiliang Li Yuan Sun Minyi Ding Yong Wang Yongliang Zhao Yan Wu Weijuan Shang Xiaming Jiang Jiwei Shan Zihao Shen Yi Tong Liuxin Xu Yu Chen Yingle Liu Gang Zou Dimitri Lavillette Zhenjiang Zhao Rui Wang Lili Zhu Gengfu Xiao Ke Lan Honglin Li Ke Xu | 2022 | Protein & Cell2022，13，10： | 0 |
| 4 | Correction to: Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2显示文摘Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument. | Rui Xiong Leike Zhang Shiliang Li Yuan Sun Minyi Ding Yong Wang Yongliang Zhao Yan Wu Weijuan Shang Xiaming Jiang Jiwei Shan Zihao Shen Yi Tong Liuxin Xu Yu Chen Yingle Liu Gang Zou Dimitri Lavillete Zhenjiang Zhao Rui Wang Lili Zhu Gengfu Xiao Ke Lan Honglin Li Ke Xu | 2021 | Protein & Cell2021，12，1： | 0 |
| 5 | UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGCip in hepatocellular carcinoma显示文摘The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients. | Junjie Xu Lin Ji Yeling Ruan Zhe Wan Zhongjie Lin Shunjie Xia Liye Tao Junhao Zheng Liuxin Cai Yifan Wang Xiao Liang Xiujun Cai | 2021 | Signal Transduction and Targeted Therapy2021，6，6： | 0 |
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