@article{8a1366064385400fa8eeb0dbab10b20e,
title = "Ferroptosis is a lysosomal cell death process",
abstract = "Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regulator of ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Activation of the MAPK/ERK pathway, but not inhibition of system Xc−, was required for STAT3 activation during erastin-induced ferroptosis. Importantly, pharmacological inhibition and genetic silencing of STAT3 through small molecules (e.g., cryptotanshinone and S3I-201) or siRNA blocked erastin-induced ferroptosis in PDAC cells. Mechanically, STAT3-mediated cathepsin B expression was required for ferroptosis. Consequently, inhibition of lysosome-dependent cell death by pharmacological blockade of cathepsin activity (using CA-074Me) or vacuolar type H+-ATPase (using bafilomycin A1) limited erastin-induced ferroptosis. These studies indicate that ferroptosis is a lysosomal cell death process.",
keywords = "Autophagy, Cathepsin, Ferroptosis, Lysosomal cell death, STAT3",
author = "Huan Gao and Yuansong Bai and Yuanyuan Jia and Yanan Zhao and Rui Kang and Daolin Tang and Enyong Dai",
note = "Funding Information: We thank Christine Burr (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health ( R01GM115366 , R01CA160417 , and R01CA211070 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the Natural Science Foundation of Jilin Province ( 20160101062JC ), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435, 81772508 , 30870355 , and 81370497 ), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), International Scientific and Technology Cooperation Program of China ( 2015DFA31490 ), and the Health Foundation of Finance Department of Jilin Province ( sczsy201516 ). Funding Information: We thank Christine Burr (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (R01GM115366, R01CA160417, and R01CA211070), the Natural Science Foundation of Guangdong Province (2016A030308011), the Natural Science Foundation of Jilin Province (20160101062JC), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81772508, 30870355, and 81370497), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), International Scientific and Technology Cooperation Program of China (2015DFA31490), and the Health Foundation of Finance Department of Jilin Province (sczsy201516). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "10",
doi = "10.1016/j.bbrc.2018.07.078",
language = "English (US)",
volume = "503",
pages = "1550--1556",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",
}