Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury

Jing Li; Qi Huang; Minling Lv; Wenfeng Ma; Jialing Sun; Xin Zhong; Rui Hu; MengQing Ma; Zhiyi Han; Wei Zhang; Wenxing Feng; Xinfeng Sun; Xiaozhou Zhou

doi:10.1038/s41420-023-01481-3

Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury

Cell Death Discov. 2023 Jun 23;9(1):189. doi: 10.1038/s41420-023-01481-3.

Authors

Jing Li^#^{1

2

3}, Qi Huang^#^{1

2}, Minling Lv^#^{1

2}, Wenfeng Ma^{1

2}, Jialing Sun^{1

2}, Xin Zhong^{1

2}, Rui Hu^{1

2}, MengQing Ma^{1

2}, Zhiyi Han^{1

2}, Wei Zhang^{1

2}, Wenxing Feng^{1

2}, Xinfeng Sun^{1

2}, Xiaozhou Zhou^{4

5}

Affiliations

¹ Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China.
² Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China.
³ Macau University of Science and Technology, Faculty of Chinese Medicine, Taipa, Macao, 999078, China.
⁴ Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China. zxz1006@gzucm.edu.cn.
⁵ Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China. zxz1006@gzucm.edu.cn.

^# Contributed equally.

Abstract

Acute liver injury (ALI) is an acute inflammatory liver disease with a high mortality rate. Alternatively, activated macrophages (AAMs) have been linked to the inflammation and recovery of ALI. However, the mechanism underlying AAM death in ALI has not been studied sufficiently. We used liensinine (Lie) as a drug of choice after screening a library of small-molecule monomers with 1488 compounds from traditional Chinese remedies. In ALI, we evaluated the potential therapeutic effects and underlying mechanisms of action of the drug in ALI and found that it effectively inhibited RSL3-induced ferroptosis in AAM. Lie significantly reduced lipid peroxidation in RSL3-generated AAM. It also improved the survival rate of LPS/D-GalN-treated mice, reduced serum transaminase activity, suppressed inflammatory factor production, and may have lowered AAM ferroptosis in ALI. Lie also inhibited ferritinophagy and blocked Fe²⁺ synthesis. Following combined treatment with RSL3 and Lie, super-resolution microscopy revealed a close correlation between ferritin and LC3-positive vesicles in the AAM. The co-localization of ferritin and LC3 with LAMP1 was significantly reduced. These findings suggest that Lie may ameliorate ALI by inhibiting ferritinophagy and enhancing AMM resistance to ferroptosis by inhibiting autophagosome-lysosome fusion. Therefore, Lie may be used as a potential therapeutic agent for patients with ALI.