This study investigates the relationship between hypoxia, ferroptosis, and miscarriage, focusing on the role of lncRNA lnc-HZ06. Hypoxia, a common feature in mammalian cells, is associated with trophoblast cell dysfunctions and miscarriage. The study found that hypoxia induces ferroptosis in human trophoblast cells, leading to miscarriage. A novel lncRNA, lnc-HZ06, was identified as a regulator of hypoxia, ferroptosis, and miscarriage. Mechanistically, HIF1α-SUMO, rather than HIF1α itself, acts as a transcription factor to promote NCOA4 transcription in hypoxic trophoblast cells. Lnc-HZ06 promotes HIF1α-SUMOylation by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acts as a transcription factor to promote lnc-HZ06 transcription, forming a positive auto-regulatory feedback loop. This loop is up-regulated in hypoxic trophoblast cells, RM villous tissues, and placental tissues of hypoxia-treated mice, further inducing ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Knockdown of either murine lnc-hz06 or Ncoa4 efficiently suppresses ferroptosis and alleviates miscarriage in a hypoxic mouse model. This study provides new insights into the regulatory roles of the lnc-HZ06/HIF1α-SUMO/NCOA4 axis in hypoxia, ferroptosis, and miscarriage, offering a potential therapeutic approach for treating unexplained miscarriage.This study investigates the relationship between hypoxia, ferroptosis, and miscarriage, focusing on the role of lncRNA lnc-HZ06. Hypoxia, a common feature in mammalian cells, is associated with trophoblast cell dysfunctions and miscarriage. The study found that hypoxia induces ferroptosis in human trophoblast cells, leading to miscarriage. A novel lncRNA, lnc-HZ06, was identified as a regulator of hypoxia, ferroptosis, and miscarriage. Mechanistically, HIF1α-SUMO, rather than HIF1α itself, acts as a transcription factor to promote NCOA4 transcription in hypoxic trophoblast cells. Lnc-HZ06 promotes HIF1α-SUMOylation by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acts as a transcription factor to promote lnc-HZ06 transcription, forming a positive auto-regulatory feedback loop. This loop is up-regulated in hypoxic trophoblast cells, RM villous tissues, and placental tissues of hypoxia-treated mice, further inducing ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Knockdown of either murine lnc-hz06 or Ncoa4 efficiently suppresses ferroptosis and alleviates miscarriage in a hypoxic mouse model. This study provides new insights into the regulatory roles of the lnc-HZ06/HIF1α-SUMO/NCOA4 axis in hypoxia, ferroptosis, and miscarriage, offering a potential therapeutic approach for treating unexplained miscarriage.