ACAA2 suppresses aerobic glycolysis and tumor growth by facilitating mitochondrial pyruvate transport in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy characterized by high incidence and mortality rates, representing a major global health challenge. Mounting evidence indicates that metabolic reprogramming contributes substantially to tumor development by promoting cancer cell proliferation and metastasis. However, the underlying mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a mitochondrial enzyme that catalyzes the final step of fatty acid β-oxidation, plays a key role in cellular acetyl-CoA homeostasis. While acetyl-CoA acts as a pivotal metabolic molecule involved in protein acetylation, whether ACAA2 regulates metabolic reprogramming through acetyl-CoA-mediated mitochondrial protein acetylation remains unclear. In this study, we demonstrate that ACAA2 expression is significantly downregulated in HCC tissues and correlates with poor patient prognosis. Downregulation of ACAA2 promotes HCC cell proliferation and survival without affecting invasive capacity. Mechanistically, ACAA2 downregulation reduces mitochondrial acetyl-CoA levels, thereby decreasing mitochondrial pyruvate carrier 1 (MPC1) acetylation and accelerating its proteasomal degradation, which ultimately impairs mitochondrial pyruvate transport to promote glycolysis and cell proliferation. Collectively, our findings demonstrate a critical tumor-suppressive function of ACAA2 in HCC and suggest it as a potential therapeutic target for the treatment of this malignancy.