L-2-hydroxyglutarate modulates ferroptosis through Nrf2/Slc7a11 and Atf4/Chac1 axes in hepatocellular carcinoma

Liver tumors undergo profound metabolic reprogramming to support survival, proliferation, and metastasis. Through a metabolic library screen combined with network-level integration of transcriptomic and metabolomic data, we identified a regulatory role of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and its substrate, L-2-hydroxyglutarate (L2HG), on ferroptosis in hepatocellular carcinoma (HCC), which exhibits a metabolic environment prone to L2HG accumulation. Mechanistically, L2HG was found to promote chromatin accessibility at ferroptosis-related gene loci. Specifically, L2HG conferred protection against ferroptosis by enhancing cystine uptake via NRF2/SLC7A11 activation, while concurrently sensitizing cells to ferroptosis through glutathione degradation via ATF4/CHAC1 induction. The ferroptosis-protective effect of L2HG was dependent on NRF2, the ablation of which restored near-normal metabolic profiles in a spontaneous liver tumor mouse model. These findings suggest that the metabolically accumulated L2HG plays a dual role in modulating both ferroptosis resistance and sensitivity, thereby influencing liver tumorigenesis. Targeting these metabolic axes may provide novel strategies for ferroptosis-based antitumor therapies.