LAMTOR2 Reprograms Energy Metabolism to Sustain Hepatocellular Carcinoma Cell Survival.

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming to support rapid proliferation and survival under nutrient stress. However, the central regulatory hubs that coordinate these diverse metabolic programs remain poorly understood. Here, we identify LAMTOR2 as a critical coordinator of energy metabolism and survival in HCC cells. LAMTOR2 is markedly upregulated in HCC tissues, and high LAMTOR2 expression correlates with poor survival. LAMTOR2 depletion inhibits HCC cell proliferation and induces significant cell death, effects that are substantially rescued by LAMTOR2 reconstitution. Mechanistically, LAMTOR2 deficiency suppresses mTORC1 signaling, leading to the concomitant downregulation of HIF1α and PPARα transcriptional activities. This dual inhibition disrupts both glycolytic flux and fatty acid β-oxidation, resulting in an energy deficit and the consequent persistent activation of the AMPK-ULK1 axis, thereby leading to autophagic cell death. Our findings identify LAMTOR2 as a pivotal oncogenic regulator that maintains HCC metabolic homeostasis, suggesting that targeting the LAMTOR2-mediated metabolic network may offer a promising therapeutic strategy for HCC.