ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1

Zhang and colleagues report a function of the glycolytic enzyme alpha-Enolase 1 in iron homeostasis. In this setting it promotes the mRNA decay of IRP1, thereby suppressing ferroptosis in hepatocellular carcinoma. alpha-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.

Automated summary

This study demonstrates the role of the glycolytic enzyme alpha-Enolase 1 in iron homeostasis and suppression of ferroptosis in hepatocellular carcinoma. The researchers found that ENO1 suppresses IRP1 expression to regulate iron balance in HCC cells, suggesting a potential innovative cancer therapy targeting the ENO1-IRP1-Mfrn1 pathway.