2021 Vol. 12, No. 11

Ionizing radiation induces ACSL4-dependent lipid ROS to kill tumor cells through ferroptosis. Certain tumors exhibit strong defense systems to lipid ROS, for example, by upregulating SLC7A11 or GPX4 (as indicated by the shield held by soldiers), resulting in radioresistance. See our review for detailed discussion.

Looking at nerves, seeing the mind: Yu-Chuan Tsang as a modern Chinese physiological psychologist
Shiying Li, Wei Chen, Shengjun Wen
2021, 12(11): 825-831. doi: 10.1007/s13238-020-00798-4
Convergent evolution of SARS-CoV-2 in human and animals
Hang-Yu Zhou, Cheng-Yang Ji, Hang Fan, Na Han, Xiao-Feng Li, Aiping Wu, Cheng-Feng Qin
2021, 12(11): 832-835. doi: 10.1007/s13238-021-00847-6
Ferroptosis, radiotherapy, and combination therapeutic strategies
Guang Lei, Chao Mao, Yuelong Yan, Li Zhuang, Boyi Gan
2021, 12(11): 836-857. doi: 10.1007/s13238-021-00841-y
Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.
Research articles
RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes
Xiang Li, Chuan-Qi Zhong, Rui Wu, Xiaozheng Xu, Zhang-Hua Yang, Shaowei Cai, Xiurong Wu, Xin Chen, Zhiyong Yin, Qingzu He, Dianjie Li, Fei Xu, Yihua Yan, Hong Qi, Changchuan Xie, Jianwei Shuai, Jiahuai Han
2021, 12(11): 858-875. doi: 10.1007/s13238-020-00810-x
There remains a significant gap in our quantitative understanding of crosstalk between apoptosis and necroptosis pathways. By employing the SWATH-MS technique, we quantified absolute amounts of up to thousands of proteins in dynamic assembling/de-assembling of TNF signaling complexes. Combining SWATH-MS-based network modeling and experimental validation, we found that when RIP1 level is below~1000 molecules/cell (mpc), the cell solely undergoes TRADD-dependent apoptosis. When RIP1 is above~1000 mpc, pro-caspase-8 and RIP3 are recruited to necrosome respectively with linear and nonlinear dependence on RIP1 amount, which well explains the co-occurrence of apoptosis and necroptosis and the paradoxical observations that RIP1 is required for necroptosis but its increase down-regulates necroptosis. Higher amount of RIP1 (>~46,000 mpc) suppresses apoptosis, leading to necroptosis alone. The relation between RIP1 level and occurrence of necroptosis or total cell death is biphasic. Our study provides a resource for encoding the complexity of TNF signaling and a quantitative picture how distinct dynamic interplay among proteins function as basis sets in signaling complexes, enabling RIP1 to play diverse roles in governing cell fate decisions.
High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors
Yao Zhao, Xiaoyu Du, Yinkai Duan, Xiaoyan Pan, Yifang Sun, Tian You, Lin Han, Zhenming Jin, Weijuan Shang, Jing Yu, Hangtian Guo, Qianying Liu, Yan Wu, Chao Peng, Jun Wang, Chenghao Zhu, Xiuna Yang, Kailin Yang, Ying Lei, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Lei Sun, Leike Zhang, Zihe Rao, Haitao Yang
2021, 12(11): 876-887. doi: 10.1007/s13238-021-00836-9
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
Deciphering primate retinal aging at single-cell resolution
Si Wang, Yuxuan Zheng, Qingqing Li, Xiaojuan He, Ruotong Ren, Weiqi Zhang, Moshi Song, Huifang Hu, Feifei Liu, Guoqiang Sun, Shuhui Sun, Zunpeng Liu, Yang Yu, Piu Chan, Guo-Guang Zhao, Qi Zhou, Guang-Hui Liu, Fuchou Tang, Jing Qu
2021, 12(11): 888-897. doi: 10.1007/s13238-020-00791-x
Precise genome editing without exogenous donor DNA via retron editing system in human cells
Xiangfeng Kong, Zikang Wang, Renxia Zhang, Xing Wang, Yingsi Zhou, Linyu Shi, Hui Yang
2021, 12(11): 898-902. doi: 10.1007/s13238-021-00862-7