Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis
Peng Tian,
Zhongyan Xu,
Jiarong Guo,
Jingsong Zhao,
Weina Chen,
Wenxin Huang,
Manli Wang,
Chenyang Mi,
Ying Zhang,
Yang Yang,
Huidong Zhang
Affiliations
Peng Tian
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, China
Zhongyan Xu
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, China
Jiarong Guo
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, China
Jingsong Zhao
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Weina Chen
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Wenxin Huang
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Manli Wang
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Chenyang Mi
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Ying Zhang
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Yang Yang
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China
Huidong Zhang
Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Corresponding author.
Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage.
