Ferritin light chain deficiency-induced ferroptosis is involved in preeclampsia pathophysiology by disturbing uterine spiral artery remodelling
Xiaofeng Yang,
Yuzhen Ding,
Lu Sun,
Meiting Shi,
Ping Zhang,
Zhengrui Huang,
Jingyun Wang,
Andong He,
Jian Wang,
Jiachun Wei,
Mengyuan Liu,
Jia Liu,
Guang Wang,
Xuesong Yang,
Ruiman Li
Affiliations
Xiaofeng Yang
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Yuzhen Ding
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Lu Sun
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Meiting Shi
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Ping Zhang
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Zhengrui Huang
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Jingyun Wang
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Andong He
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Jian Wang
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Jiachun Wei
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Mengyuan Liu
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Jia Liu
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China
Guang Wang
International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China; The corresponding author.
Xuesong Yang
International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China; Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, 510632, China; The corresponding author. International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China.
Ruiman Li
Department of Obstetrics and Gynecology, The First Affiliate Hospital of Jinan University, Guangzhou, 510630, China; The corresponding author.
The proteomic analysis from samples of patients with preeclampsia (PE) displayed a low level of ferritin light chains (FTL), but we do not know what the significance of reduced FTL in PE pathophysiology is. To address this question, we first demonstrated that FTL was expressed in first- and third-trimester cytotrophoblasts, including extravillous trophoblasts (EVTs), of the human placenta. Furthermore, a pregnant rat model of FTL knockdown was successfully established by intravenously injecting adenoviruses expressing shRNA targeting FTL. In pregnant rats with downregulated FTL, we observed PE-like phenotypes and impaired spiral arterial remodelling, implying a causal relationship between FTL downregulation and PE. Blocking ferroptosis with ferrostatin-1 (Fer-1) significantly rescued the above PE-like phenotypes in pregnant rats with FTL knockdown. Furthermore, using trophoblast cell line and chorionic villous explant culture assays, we showed that FTL downregulation induced cell death, especially ferroptosis, resulting in defective uterine spiral artery remodelling. Eventually, this conclusion from the animal model was verified in PE patients’ placental tissues. Taken together, this study revealed for the first time that FTL reduction during pregnancy triggered ferroptosis and then caused defective uterine spiral artery remodelling, thereby leading to PE.
