Acadl, encoding long-chain acyl-CoA dehydrogenase, is a key enzyme for catalyzing fatty acid oxidation, playing a pivotal role in lipid metabolism pathways [1,2,3,4]. It is involved in the initial step of mitochondrial fatty acid oxidation, which is essential for energy production from fatty acids [1,5,6,8]. Genetic models, such as Acadl -deficient mouse models, are valuable tools for studying its functions [9].

In hepatocellular carcinoma (HCC), increased extracellular matrix stiffness activates YAP/TEAD4 transcriptional complex, which directly represses Acadl transcription. Acadl is regarded as a tumor suppressor in HCC, and its reduced expression is associated with metastasis and poor prognosis. Upregulation of Acadl inhibits HCC migration and invasion by negatively regulating matrix metalloproteinase-14 (MMP14) through the STAT3 signaling pathway [1,5].

In cardiac hypertrophy in male mice, the KLF7/PFKL/Acadl axis modulates cardiac metabolic remodelling. Cardiac-specific knockout of KLF7, which targets Acadl, induces adult concentric hypertrophy by regulating fatty acid oxidation [2].

In goat intramuscular and subcutaneous adipocytes, overexpression of Acadl promotes adipocyte differentiation, while interference inhibits it [3,4].

In non-small cell lung cancer (NSCLC) and lung adenocarcinoma (LUAD), Acadl also acts as a tumor suppressor. In NSCLC, overexpression of Acadl reduces cell proliferation, invasion, and colony formation by modulating YAP phosphorylation. In LUAD, Acadl inhibits proliferation, enhances apoptosis, and prevents tumor immune evasion by suppressing PD-L1 expression through the Hippo/YAP pathway [6,7].

In conclusion, Acadl is crucial for fatty acid oxidation and lipid metabolism. Studies using gene-knockout or conditional-knockout mouse models have revealed its significant roles in multiple disease areas, including cancer and cardiac hypertrophy. These findings provide insights into potential therapeutic strategies targeting Acadl for treating related diseases.