Hydrogen sulfide (H 2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H 2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H 2 regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H 2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of low-density lipoprotein receptor (LDLR) in a time- and dose-dependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate-labeled LDL (DiI-LDL) uptake in the H 2S-treated HepG2 cells. Furthermore, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-sterol regulatory element binding proteins 2 (SREBP-2) signaling pathway was confirmed to be involved in H 2S-regulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiI-LDL for 24 h, and the results revealed that H 2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H 2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/Akt-SREBP-2 signaling pathway. To the very best of our knowledge, this study is the first to report that H 2S can regulate the expression of PCSK9.