Dihydroartemisinin eliminates senescent cells by promoting autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.

Autor: Wan X; Department of Pediatrics, School of Clinical Medicine, Southwest Medical University, Luzhou, China.; Department of Pediatrics, Chengdu Third People's Hospital, Chengdu, Sichuan, China., Li C; Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu, China., Tan YH; Department of Inspection Technology, Sichuan Nursing Vocational College, Chengdu, China., Zuo SQ; Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China., Deng FM; Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China., Sun J; Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China., Liu YL; Department of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
Jazyk: angličtina
Zdroj: Cell biology international [Cell Biol Int] 2024 May; Vol. 48 (5), pp. 726-736. Date of Electronic Publication: 2024 Mar 04.
DOI: 10.1002/cbin.12143
Abstrakt: Cellular senescence is an irreversible cell-cycle arrest in response to a variety of cellular stresses, which contribute to the pathogenesis of a variety of age-related degenerative diseases. However, effective antisenescence strategies are still lacking. Drugs that selectively target senescent cells represent an intriguing therapeutic strategy to delay aging and age-related diseases. Thus, we thought to investigate the effects of dihydroartemisinin (DHA) on senescent cells and elucidated its mechanisms underlying aging. Stress-induced premature senescence (SIPS) model was built in NIH3T3 cells using H 2 O 2 and evaluated by β-galactosidase staining. Cells were exposed to DHA and subjected to cellular activity assays including viability, ferroptosis, and autophagy. The number of microtubule-associated protein light-chain 3 puncta was detected by immunofluorescence staining. The iron content was assessed by spectrophotometer and intracellular reactive oxygen species (ROS) was measured by fluorescent probe dichlorodihydrofluorescein diacetate. We found that DHA triggered senescent cell death via ferroptosis. DHA accelerated ferritin degradation via promoting autophagy, increasing the iron contents, promoting ROS accumulation, thus leading to ferroptotic cell death in SIPS cells. In addition, autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. Moreover, Atg5 silencing and autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. We also revealed that the expression of p-AMP-activated protein kinase (AMPK) and p-mammalian target of rapamycin (mTOR) in senescent cells was downregulated. These results suggested that DHA may be a promising drug candidate for clearing senescent cells by inducing autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.
(© 2024 International Federation for Cell Biology.)
Databáze: MEDLINE
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