Acylphosphatase 1 (ACYP1), a
protein located in the mammalian cell cytoplasm, has been shown to be associated with
tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to
lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo.
RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the
malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its
tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc
protein expression and stability by ACYP1 is HSP90 dependent. Importantly,
lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases
lenvatinib resistance and inhibits progression of HCC
tumors with high ACYP1 expression when combined with
lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives
lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with
lenvatinib to treat HCC more effectively.