Hypoxia-driven lncRNA SHIELD promotes GPX4 translation and protects against ferroptosis in hepatocellular carcinoma.

Targeting ferroptosis, a form of regulated cell death, holds potential for improving treatment efficacy in a range of cancers including hepatocellular carcinoma (HCC). The selenoprotein glutathione peroxidase 4 (GPX4) plays a crucial role in suppressing ferroptosis by converting toxic phospholipid hydroperoxides into non-toxic lipid alcohols, yet the mechanisms regulating its synthesis remain poorly understood. This study identifies SHIELD (suppressor of hypoxia-induced lipid peroxidation and death), a long noncoding RNA (lncRNA) and direct HIF-1α target, as a regulator of ferroptosis in HCC. SHIELD inhibits ferroptosis by interacting with the RNA-binding protein GRSF1, which forms a ternary complex with GPX4 5'-UTR to enhance GPX4 mRNA translation and expression. Furthermore, targeting SHIELD with antisense oligonucleotides (ASOs) in combination with sorafenib significantly reduced tumor growth in patient-derived xenograft models. This discovery paves the way for improving the efficacy of tyrosine kinase inhibitors in HCC, which addresses the challenge of therapeutic resistance.