This study investigates the role of ferroptosis in lipopolysaccharide (LPS)-induced inflammation in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) under hypoxic conditions. The researchers found that LPS activates ferroptosis in RA FLSs by increasing cellular damage, reactive oxygen species (ROS), lipid peroxidation, intracellular iron, and inflammatory cytokines (IL6 and IL8). Ferroptosis can be further amplified by ferroptosis inducers (erastin and RSL-3) and inhibited by ferroptosis inhibitors (Fer-1 and DFO). Mechanistically, LPS triggers ferroptosis via NCOA4-mediated ferritinophagy, and knocking down NCOA4 prevents this process. Notably, LPS-induced RA FLSs become less sensitive to ferroptosis and NCOA4-mediated ferritinophagy under hypoxia compared to normoxia. Knocking down HIF-1α reverses ferroptosis and ferritinophagy evoked by LPS-induced inflammation under hypoxia. Additionally, low doses of auranofin (AUR) induce re-sensitization of ferroptosis and ferritinophagy by inhibiting HIF-1α expression under hypoxia. The study concludes that NCOA4-mediated ferritinophagy is a key driver of ferroptosis in inflammatory RA FLSs, and targeting HIF-1α/NCOA4 and ferroptosis could be a valuable therapeutic strategy for synovium hyperplasia in RA patients.This study investigates the role of ferroptosis in lipopolysaccharide (LPS)-induced inflammation in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) under hypoxic conditions. The researchers found that LPS activates ferroptosis in RA FLSs by increasing cellular damage, reactive oxygen species (ROS), lipid peroxidation, intracellular iron, and inflammatory cytokines (IL6 and IL8). Ferroptosis can be further amplified by ferroptosis inducers (erastin and RSL-3) and inhibited by ferroptosis inhibitors (Fer-1 and DFO). Mechanistically, LPS triggers ferroptosis via NCOA4-mediated ferritinophagy, and knocking down NCOA4 prevents this process. Notably, LPS-induced RA FLSs become less sensitive to ferroptosis and NCOA4-mediated ferritinophagy under hypoxia compared to normoxia. Knocking down HIF-1α reverses ferroptosis and ferritinophagy evoked by LPS-induced inflammation under hypoxia. Additionally, low doses of auranofin (AUR) induce re-sensitization of ferroptosis and ferritinophagy by inhibiting HIF-1α expression under hypoxia. The study concludes that NCOA4-mediated ferritinophagy is a key driver of ferroptosis in inflammatory RA FLSs, and targeting HIF-1α/NCOA4 and ferroptosis could be a valuable therapeutic strategy for synovium hyperplasia in RA patients.