However, the underlying mechanism that PPARγ mediated hypoxia-induced HSC activation must be further explored. Recent studies displayed that AKT signaling and PPARγ have a mutual inhibitory effect [25–27], but this theory is still controversial. Kilter et al. suggested that PPARγ facilitates AKT phosphorylation in cardiomyocytes during hypoxia/reoxygenation . However, another independent study found that PPARγ inhibits endothelial cell migration by inhibiting PI3K/AKT signaling . Our present study showed that PI3K/AKT signaling blocked the inhibitory effect of PPARγ on hypoxia-induced HSCs activation. Next, cGMP analogs and antagonists were used, and results showed that sGC/cGMP/PKG directly inhibited PI3K/AKT signaling and increased PPARγ expression, eventually affecting the hypoxia-induced HSCs activation. In contrast, inhibition of PDE5 and resisting cGMP hydrolysis restore cGMP and PKG activity, followed by increased PPARγ expression and repressed HSCs activation.