Ferroptosis, an iron-dependent form of cell death, plays a role in inflammatory arthritis. This study investigated the role of ferroptosis in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) under hypoxia. RA FLSs were treated with lipopolysaccharide (LPS) and ferroptosis inducers (erastin and RSL-3), or inhibitors (Fer-1 and DFO). LPS activated ferroptosis by increasing ROS, lipid peroxidation, and iron levels. NCOA4-mediated ferritinophagy was involved in this process, and its knockdown prevented ferroptosis. Under hypoxia, LPS-induced RA FLSs became resistant to ferroptosis, but this resistance was reversed by knocking down HIF-1α. Auranofin (AUR) re-sensitized RA FLSs to ferroptosis by inhibiting HIF-1α. These findings suggest that NCOA4-mediated ferritinophagy is a key driver of ferroptosis in RA FLSs under hypoxia. Targeting HIF-1α/NCOA4 and ferroptosis could be a therapeutic strategy for RA synovial hyperplasia. Ferroptosis is regulated by HIF-1α, which controls iron metabolism genes such as TfR, FPN, and FTH. NCOA4, regulated by HIF-1α, mediates ferritinophagy, releasing iron that leads to ferroptosis. AUR, an FDA-approved RA drug, may target ferroptosis in RA by inhibiting HIF-1α. This study suggests that targeting ferroptosis could be a novel therapeutic approach for RA.Ferroptosis, an iron-dependent form of cell death, plays a role in inflammatory arthritis. This study investigated the role of ferroptosis in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) under hypoxia. RA FLSs were treated with lipopolysaccharide (LPS) and ferroptosis inducers (erastin and RSL-3), or inhibitors (Fer-1 and DFO). LPS activated ferroptosis by increasing ROS, lipid peroxidation, and iron levels. NCOA4-mediated ferritinophagy was involved in this process, and its knockdown prevented ferroptosis. Under hypoxia, LPS-induced RA FLSs became resistant to ferroptosis, but this resistance was reversed by knocking down HIF-1α. Auranofin (AUR) re-sensitized RA FLSs to ferroptosis by inhibiting HIF-1α. These findings suggest that NCOA4-mediated ferritinophagy is a key driver of ferroptosis in RA FLSs under hypoxia. Targeting HIF-1α/NCOA4 and ferroptosis could be a therapeutic strategy for RA synovial hyperplasia. Ferroptosis is regulated by HIF-1α, which controls iron metabolism genes such as TfR, FPN, and FTH. NCOA4, regulated by HIF-1α, mediates ferritinophagy, releasing iron that leads to ferroptosis. AUR, an FDA-approved RA drug, may target ferroptosis in RA by inhibiting HIF-1α. This study suggests that targeting ferroptosis could be a novel therapeutic approach for RA.