# Malic enzyme 1 contributes to tumorigenesis and lenvatinib resistance in hepatocellular carcinoma via FSP1-dependent ferroptosis evasion

## TL;DR

Malic enzyme 1 (ME1) promotes liver cancer growth and drug resistance by helping cancer cells avoid a type of cell death called ferroptosis.

## Contribution

The study identifies ME1 as a novel driver of HCC progression and lenvatinib resistance through the NADPH-FSP1-CoQH2 pathway.

## Key findings

- ME1 is upregulated in HCC and correlates with poor prognosis.
- ME1 promotes HCC cell viability and tumor growth in mice.
- ME1 overexpression causes lenvatinib resistance, which is reversed by ME1 knockout.

## Abstract

Hepatocellular carcinoma (HCC) is the most prevalent hepatic malignancy worldwide, accounting for approximately 90% of all primary liver cancer cases. However, the mechanisms involving in liver tumorigenesis and drug resistance remain unclear, largely restricting the clinical management of HCC. Here, we first evaluated the clinical significance of malic enzyme 1 (ME1) in HCC patients and revealed that ME1 was significantly upregulated in tumor tissues and positively correlated with poor prognosis. Gain- and loss-of-function experiments suggested that ME1 promoted HCC cell viability in vitro. Consistently, hepatocyte-specific Me1 knockout (Me1HKO) mice treated with diethylnitrosamine (DEN) showed reduced tumor burden as compared to Me1Flox mice. In addition, ME1 overexpression conferred resistance to the first-line therapeutic drug lenvatinib, while knockout of ME1 restored drug sensitivity in lenvatinib-resistant HCC cells. Mechanistically, we showed that ME1 could regulate ferroptosis of HCC cells through its function on NADPH production. We further identified ferroptosis suppressor protein 1 (FSP1) as a key downstream effector, which utilized ubiquinol (CoQH2) as a lipophilic radical-trapping antioxidant to block the accumulation of lipid peroxides to pro-ferroptotic levels. In summary, our findings demonstrated that ME1 promotes HCC progression by activating the NADPH-FSP1-CoQH2 axis and thereby inhibiting ferroptosis, suggesting a promising therapeutic strategy for HCC treatment.