Fig. 9

Schematic representation of YC-1 with PA + LC treatment to target hypoxic within HCC tumors. A Reprograming of fatty acid metabolism by HIF-1α in hypoxic regions within HCC tumors. HIF-1α inhibits gene expression of CD36, ACSL-1, CPT-1A, MCAD, and LCAD, leading to suppressed fatty acid β-oxidation (FAO) activity in hypoxic HCC cells. In contrast, HIF-1α induces expression of AGPAT and DGAT to promote triglyceride (TG) synthesis and increases lipid droplets in hypoxic HCC cells. B The lipo-apoptotic effect of YC-1 with PA + LC treatment on hypoxic HCC cells. Inhibition of HIF-1α expression by YC-1 increases fatty acid uptake and elevates FAO activity in hypoxic HCC cells by restoring expression of CD36 and FAO-related enzymes, respectively. Additionally, inhibited HIF-1α expression by YC-1 suppresses hypoxic upregulation of AGPAT and DGAT, leading to reduced TG synthesis. Taken together, YC-1 treatment causes forced activation of FAO and leads to lethal reactive oxygen species (ROS) production through TCA cycle to ETC axis in hypoxic HCC cells. Moreover, additional treatment with PA plus LC further promotes FAO activity, increases ROS production, and synergistically enhances cell apoptosis