4.6 Article

Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis

Journal

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2020.12.066

Keywords

Autophagy; DNA damage; Ferroptosis; HMGB1; Nucleus; Pirin

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This study reveals the role of the nuclear protein pirin in mediating resistance to ferroptosis in human pancreatic cancer cells. The upregulation of PIR by the transcription factor NFE2L2 during ferroptosis limits oxidative damage and HMGB1 release, while depletion of PIR initiates autophagy and promotes ferroptosis through ACSL4 activation. Blocking PIR signaling enhances ferroptosis-induced tumor growth suppression, providing new insights into the molecular mechanisms of autophagy-dependent ferroptosis.
In regulated cell death, genetically encoded molecular machinery destroys cells. This process is not only essential for organ development and homeostasis, but also leads to pathological diseases. One form of regulated cell death is ferroptosis, which is an iron-dependent oxidative cell death caused by lipid peroxidation. Although inducing ferroptosis is an emerging anticancer strategy, the molecular mechanism underlying tumor resistance to ferroptotic cell death is still unclear. Here, we show that pirin (PIR), an iron-binding nuclear protein, plays a previously unrecognized role in mediating ferroptosis resistance in human pancreatic cancer cells. The transcription factor NFE2L2 mediates the upregulation of PIR during ferroptosis caused by small-molecule compounds (e.g., erastin or RSL3). PIR is a nuclear redox sensor and regulator, and increasing it limits the oxidative damage of DNA and the subsequent cytoplasmic transport and extracellular release of HMGB1. In contrast, the depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4. Consequently, in cell cultures and xenograft mouse models, blocking PIR signaling enhances ferroptosis-mediated tumor growth suppression. Together, these findings provide new insights into the molecular mechanisms of autophagy-dependent ferroptosis. (C) 2020 Elsevier Inc. All rights reserved.

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