# LncRNA-PRLB drives ovarian cancer progression and chemoresistance by stabilizing GPX4 mRNA through the FUS-mediated suppression of ferroptosis

## TL;DR

This study shows that lncRNA-PRLB helps ovarian cancer cells resist chemotherapy by preventing a type of cell death called ferroptosis.

## Contribution

The study reveals a novel mechanism where lncRNA-PRLB stabilizes GPX4 mRNA via FUS to suppress ferroptosis and chemoresistance in ovarian cancer.

## Key findings

- LncRNA-PRLB promotes ovarian cancer cell survival and resistance to paclitaxel.
- LncRNA-PRLB binds to FUS and stabilizes GPX4 mRNA, reducing ferroptosis.
- Disrupting the lncRNA-PRLB/FUS/GPX4 axis increases sensitivity to chemotherapy.

## Abstract

Ovarian cancer is highly lethal, largely due to the rapid development of paclitaxel resistance. This study aimed to determine whether progression-associated lncRNA in breast cancer (lncRNA-PRLB) regulates ferroptosis and paclitaxel resistance in ovarian cancer and to elucidate the underlying mechanism.

Functional assays, including 5-ethynyl-2′-deoxyuridine (EdU) incorporation, Cell Counting Kit-8 (CCK-8) viability measurements, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, caspase-3 activity assays, Transwell invasion, wound healing, and ferroptosis marker analyses [reactive oxygen species (ROS), malondialdehyde MDA, Fe2+, lactate dehydrogenase (LDH), and glutathione (GSH)], were performed in CAOV3 and SKOV3 ovarian cancer cells following lncRNA-PRLB knockdown or overexpression. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D mRNA decay assays were conducted to elucidate the molecular interactions between lncRNA-PRLB, the RNA-binding protein fused in sarcoma (FUS), and glutathione peroxidase 4 (GPX4) mRNA. Rescue experiments involving GPX4 overexpression or ferrostatin-1 treatment, as well as FUS knockdown, were used to define mechanistic dependencies. Paclitaxel sensitivity assays were performed to assess chemoresistance phenotypes.

LncRNA-PRLB was identified as an oncogenic regulator that enhances ovarian cancer cell proliferation, migration, invasion, and paclitaxel resistance. Silencing lncRNA-PRLB induced apoptosis and triggered ferroptosis, characterized by elevated ROS, MDA, Fe2+, LDH release, and depletion of GSH. Mechanistically, lncRNA-PRLB directly bound to FUS and facilitated the stabilization of GPX4 mRNA, thereby maintaining GPX4 protein levels and suppressing ferroptotic signaling. GPX4 overexpression or ferroptosis inhibition rescued the phenotypes induced by lncRNA-PRLB knockdown, while FUS depletion abolished the oncogenic functions of lncRNA-PRLB. Loss of the lncRNA-PRLB/FUS/GPX4 axis sensitized ovarian cancer cells to paclitaxel, suggesting that ferroptosis suppression is a key driver of chemoresistance.

This study identifies lncRNA-PRLB as a critical upstream regulator of ferroptosis resistance and chemoresistance in ovarian cancer. By scaffolding FUS to stabilize GPX4 mRNA, lncRNA-PRLB maintains GPX4 expression and enables tumor cells to evade ferroptotic cell death.