According to previous studies, sGC/cGMP/PKG contributes to the treatment of cirrhosis. In addition, this signal also modulates various cellular events induced by hypoxic stress. To investigate the potential role of sGC/cGMP/PKG signaling in HSC hypoxia responses modulated by PPAR and PI3K/AKT signaling, HSCs were incubated for 90 min under hypoxia with or without 8-Br-cGMP (1 mM) which was widely used as sGC/cGMP/PKG agonist and in the presence or absence of Rp-8-Br-cGMP (20 μM), a sGC/cGMP/PKG antagonist. We found that cotreated 8-Br-cGMP with hypoxia showed a significant decrease in protein levels of PI3K p110α, PI3K p110β, and phosphorylated AKT in comparison with the hypoxia group. In consequence of this decline, PPARγ expression increased. Moreover, just as we speculated, α-SMA and desmin level also reduced. The effect induced by 8-Br-cGMP was blocked by the inclusion of Rp-8-Br-cGMP (Figure 4(a)). These results indicated that sGC/cGMP/PKG directly inhibited PI3K/AKT signaling and on the other hand increased PPARγ, eventually affecting the hypoxia-induced HSCs activation.