LncRNA-PRLB is an oncogenic regulator that enhances proliferation, migration, invasion, and paclitaxel resistance in ovarian cancer cells. Silencing of lncRNA-PRLB induces apoptosis and ferroptosis, characterized by increased levels of ROS, MDA, Fe2+, LDH and decreased GSH. LncRNA-PRLB directly binds to FUS protein, stabilizing GPX4 mRNA and maintaining GPX4 protein levels, which suppresses ferroptotic signaling. GPX4 overexpression or ferrostatin-1 treatment rescues the silencing effects of lncRNA-PRLB, whereas FUS knockdown abrogates its oncogenic effects. Loss of the lncRNA-PRLB/FUS/GPX4 axis increases the sensitivity of cells to paclitaxel. Study identifies lncRNA-PRLB as an upstream regulator of ferroptosis resistance and chemoresistance in ovarian cancer.