Long-chain acyl-CoA dehydrogenase (ACADL) is a mitochondrial enzyme that catalyzes the initial step of fatty acid oxidation, but the role of ACADL in tumor biology remains largely unknown. Here, we found that ACADL was frequently downregulated in hepatocellular carcinoma (HCC), and its low expression was significantly correlated with poor clinical prognosis of HCC patients. Restoring the expression of ACADL in HCC cells resulted cell cycle arrest and growth suppression through suppressing Hippo/YAP signaling evidenced by decreased YAP nuclear accumulation and downstream target genes expression. Reactivation of YAP by XMU-MP-1 diminished the inhibitory effect of ACADL on HCC growth. More importantly, the nuclear accumulation of YAP was negatively correlated with ACADL expression levels in HCC specimens, and YAP inhibitor verteporfin effectively suppressed growth of HCC organoids with low ACADL expression. Together, our findings highlight a novel function of ACADL in regulating HCC growth and targeting ACADL/Yap may be a potential strategy for HCC precise treatment.

长链酰基辅酶A脱氢酶（ACADL）是一种线粒体酶，可催化脂肪酸氧化的起始步骤，但是ACADL在肿瘤生物学中的作用仍然未知。在这里，我们发现ACADL在肝细胞癌（HCC）中经常被下调，其低表达与HCC患者的不良临床预后显着相关。恢复HCC细胞中ACADL的表达可通过抑制Hippo / YAP信号传导而导致细胞周期停滞和生长抑制，这可通过减少YAP核积累和下游靶基因表达来证明。XMU-MP-1对YAP的再激活减少了ACADL对HCC生长的抑制作用。更重要的是，在肝癌标本中，YAP的核积累与ACADL表达水平呈负相关，YAP抑制剂verteporfin可有效抑制ACADL表达低的HCC类器官的生长。总之，我们的发现突出了ACADL在调节HCC生长中的新功能，靶向ACADL / Yap可能是HCC精确治疗的潜在策略。