Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis

Masahiro Yoshida, Shunsuke Minagawa, Jun Araya, Taro Sakamoto, Hiromichi Hara, Kazuya Tsubouchi, Yusuke Hosaka, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Nahoko Sato, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Hirohumi Utsumi, Hiroshi Wakui, Takanori Numata, Yumi Kaneko, Shohei Mori, Hisatoshi AsanoMakoto Yamashita, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Takeo Iwamoto, Hirotaka Imai, Kazuyoshi Kuwano

Research output: Contribution to journalArticlepeer-review

338 Citations (Scopus)

Abstract

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

Original languageEnglish
Article number3145
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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