miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma

TLDR

Ferroptosis is an iron‑dependent, lipid‑ROS driven form of cell death distinct from apoptosis, necroptosis, and autophagy, and although miRNAs regulate many biological processes, none had been shown to modulate ferroptosis before this study. The study investigates whether miR‑137 regulates ferroptosis by directly targeting the glutamine transporter SLC1A5 in melanoma cells. Ectopic miR‑137 expression suppressed SLC1A5, reducing glutamine uptake and lipid peroxidation, while loss of miR‑137 heightened erastin‑ and RSL3‑induced ferroptosis and enhanced erastin’s antitumor effect in vitro and in vivo, demonstrating that miR‑137 inhibits ferroptosis through glutaminolysis inhibition and may serve as a therapeutic target in melanoma.

Abstract

Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes. However, to date no study has reported miRNA-mediated regulation of ferroptosis. Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells. Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation. Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis. Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo. Collectively, these data indicate that miR-137 plays a novel and indispensable role in ferroptosis by inhibiting glutaminolysis and suggest a potential therapeutic approach for melanoma.