Ferredoxin 1-like maintains iron homeostasis and hepatoma cell survival.

Ferredoxin 1-like (FDX1L) is a pivotal component of the core iron-sulfur (Fe-S) cluster assembly machinery. However, the role of FDX1L in hepatocellular carcinoma (HCC) has not been thoroughly elucidated. In this study, we conducted genome-wide CRISPR-Cas9 screenings and identified FDX1L as an essential gene for hepatoma cell survival. We found that FDX1L expression is elevated in HCC tissues compared to adjacent non-tumorous tissues, accompanied by its high expression indicating poor prognosis in HCC patients. In line with this, FDX1L knockdown markedly suppresses HCC cell survival both in vitro and in vivo. Mechanistically, Knockdown of FDX1L leads to the accumulation of lipid peroxidation and promotes ferroptosis in HCC cells. FDX1L deficiency induces inadequate maintenance of Fe-S clusters and strongly activates the iron-starvation response, leading to an upregulation of the metal transporter protein SLC39A14 and enhancement of iron influx. Consequently, FDX1L downregulation-induced iron overload results in ferroptosis in hepatoma cells. Our study provides insight into a novel role of FDX1L in iron homeostasis and the regulation of ferroptosis, underscoring its potential as a promising therapeutic target in HCC.