Hypoxia induces trophoblast cell ferroptosis, leading to miscarriage through the lnc-HZ06/HIF1α-SUMO/NCOA4 axis. This study reveals that hypoxia causes ferroptosis in human trophoblast cells, which is regulated by the lncRNA lnc-HZ06. Mechanistically, hypoxia increases HIF1α levels, which are SUMOylated to enhance NCOA4 expression, a key factor in ferroptosis. Lnc-HZ06 promotes HIF1α SUMOylation by inhibiting SENP1-mediated deSUMOylation, forming a positive feedback loop with HIF1α-SUMO. This loop enhances NCOA4 transcription, promoting ferroptosis and miscarriage. In hypoxic trophoblast cells, lnc-HZ06 and HIF1α-SUMO work together to upregulate NCOA4, leading to increased ferroptosis markers and miscarriage. In mouse models, hypoxia induces ferroptosis and miscarriage, which can be alleviated by knocking down lnc-HZ06 or NCOA4. These findings suggest that the lnc-HZ06/HIF1α-SUMO/NCOA4 axis plays a critical role in hypoxia-induced miscarriage, offering potential therapeutic strategies for unexplained recurrent miscarriage.Hypoxia induces trophoblast cell ferroptosis, leading to miscarriage through the lnc-HZ06/HIF1α-SUMO/NCOA4 axis. This study reveals that hypoxia causes ferroptosis in human trophoblast cells, which is regulated by the lncRNA lnc-HZ06. Mechanistically, hypoxia increases HIF1α levels, which are SUMOylated to enhance NCOA4 expression, a key factor in ferroptosis. Lnc-HZ06 promotes HIF1α SUMOylation by inhibiting SENP1-mediated deSUMOylation, forming a positive feedback loop with HIF1α-SUMO. This loop enhances NCOA4 transcription, promoting ferroptosis and miscarriage. In hypoxic trophoblast cells, lnc-HZ06 and HIF1α-SUMO work together to upregulate NCOA4, leading to increased ferroptosis markers and miscarriage. In mouse models, hypoxia induces ferroptosis and miscarriage, which can be alleviated by knocking down lnc-HZ06 or NCOA4. These findings suggest that the lnc-HZ06/HIF1α-SUMO/NCOA4 axis plays a critical role in hypoxia-induced miscarriage, offering potential therapeutic strategies for unexplained recurrent miscarriage.