Acetyl-CoA synthase 1 mediates metabolic reprogramming to promote proliferation and metastasis of osteosarcoma

Although the combination of surgery and chemotherapy has dramatically improved the prognosis of patients with osteosarcoma (OS), the prognosis of OS patients with metastatic or recurrent tumors remains poor. Here, we found significant upregulation of the acetyl-CoA synthesis-related pathway in OS patients with metastases.

Bioinformatics analysis identified ACSS1 as a key metastasis-related gene in OS, with clinical OS specimens validating its association with poor prognosis. In vitro, ACSS1 knockdown in 143B and SJSA1 cells was used to assess proliferation (EdU, colony formation), migration/invasion (Transwell, 3D spheroids), and mitochondrial function (Seahorse, TEM). Untargeted metabolomics and transcriptomics characterized ACSS1-regulated lipid pathways, while in vivo validation employed nude mouse models of orthotopic xenograft and tail vein metastasis.

Notably, the expression of Acetyl-coenzyme A synthetase 1 (ACSS1), an enzyme critical for acetyl-CoA synthesis, was negatively correlated with pulmonary metastasis-free and overall survival in OS patients. ACSS1 depletion decreases the metastatic ability and energy metabolism of OS cells, resulting in reactive oxygen species (ROS) accumulation. Mechanistically, ACSS1 exerts acetyl-CoA synthetase activity and maintains dynamic homeostasis of acetyl-CoA metabolism in the mitochondria. It promotes lipid synthesis and regulates metabolic homeostasis by inducing stearoyl coenzyme A desaturase (SCD) expression, which can fuel the metastasis of OS cells and promotes their survival.

ACSS1 drives OS metastasis by maintaining mitochondrial acetyl-CoA homeostasis and activating SCD-dependent lipid synthesis. Targeting the ACSS1/SCD axis offers a promising strategy for metastatic OS.

This study reveals the therapeutic potential of targeting ACSS1/SCD axis, for example, by specific small-molecule inhibitors in treating osteosarcoma metastasis, in addition to conventional chemotherapies.