title: FANCD2 protects against bone marrow injury from ferroptosis.
abstract: Bone marrow injury remains a serious concern in traditional cancer treatment. Ferroptosis is an iron- and oxidative-dependent form of regulated cell death that has become part of an emerging strategy for chemotherapy. However, the key regulator of ferroptosis in bone marrow injury remains unknown. Here, we show that Fanconi anemia complementation group D2 (FANCD2), a nuclear protein involved in DNA damage repair, protects against ferroptosis-mediated injury in bone marrow stromal cells (BMSCs). The classical ferroptosis inducer erastin remarkably increased the levels of monoubiquitinated FANCD2, which in turn limited DNA damage in BMSCs. FANCD2-deficient BMSCs were more sensitive to erastin-induced ferroptosis (but not autophagy) than FANCD2 wild-type cells. Knockout of FANCD2 increased ferroptosis-associated biochemical events (e.g., ferrous iron accumulation, glutathione depletion, and malondialdehyde production). Mechanically, FANCD2 regulated genes and/or expression of proteins involved in iron metabolism (e.g., FTH1, TF, TFRC, HAMP, HSPB1, SLC40A1, and STEAP3) and lipid peroxidation (e.g., GPX4). Collectively, these findings indicate that FANCD2 plays a novel role in the negative regulation of ferroptosis. FANCD2 could represent an amenable target for the development of novel anticancer therapies aiming to reduce the side effects of ferroptosis inducers.
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Xinxin
authors: X
authors: Song
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Yangchun
authors: Y
authors: Xie
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Rui
authors: R
authors: Kang
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Wen
authors: W
authors: Hou
authors: The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors: Xiaofang
authors: X
authors: Sun
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Michael W
authors: MW
authors: Epperly
authors: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Joel S
authors: JS
authors: Greenberger
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China. Electronic address: tangd2@upmc.edu.
authors: Daolin
authors: D
authors: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D007501:Iron
keywords: Bone marrow; DNA damage; FANCD2; Ferroptosis; Iron; Lipid peroxidation