Modulating lipid metabolism by nanoparticles (NPs)-mediated ACSL3 silencing to inhibit hepatocellular carcinoma growth and metastasis

Abnormal lipid metabolism plays an important role in the development and progression of almost all cancer types, especially hepatocellular carcinoma (HCC) as the liver is the central organ for lipid storage and metabolism. However, the underlying mechanisms are complex and have not been completely elucidated. By analyzing the proteomic sequencing and single cell RNA-sequencing (scRNA-seq) results of HCC patients, we herein reveal that acyl-CoA synthase long chain family member 3 (ACSL3) is predominately expressed in HCC cells and high ACSL3 expression is positively correlated with abnormal lipid metabolism and predicts the poor prognosis of HCC patients. Mechanically, ACSL3 could promote the synthesis of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), which could activate peroxisome proliferator-activated receptor α (PPARα) pathway and enhance the transcription of downstream lipid metabolism-associated genes, thereby promoting HCC growth and metastasis via accelerating lipid catabolism and anabolism. Considering the lack of specific inhibitor for ACSL3, we further develop an endosomal pH-responsive nanoparticle (NP) platform for systemic delivery of ACSL3 siRNA (siACSL3) and demonstrate its ability to inhibit HCC tumor growth and metastasis. Our findings indicate that ACSL3 could be used to predict the prognosis of HCC patients and NPs-mediated ACSL3 silencing could be a promising strategy for effective HCC therapy.