Figure 8.
A mechanistic scheme of HuR/HO‐1 molecular axis promoting cytoprotection through autophagy signaling in IR‐stressed mouse and human LT. In primary mouse hepatocytes exposed to warm oxidative stress, HO‐1 is regulated by HuR and not HIF‐1α. Protein expression of antiapoptotic Bcl‐xL and BMP4 increase correspondingly. By contrast, HIF‐1α but not HuR is positively correlated with HO‐1 in cold‐stored human livers and may serve as a regulator in mouse hepatocytes cultured under cold hypoxic conditions. Cold hypoxia also causes a significant decline of BMP4 but not Bcl‐2, which is correlated with HuR levels in human LT. The reperfusion triggers hepatocyte DAMPs to stimulate the release of proinflammatory cytokines/chemokines. Cytoplasmic HuR stabilization of HO‐1 3′UTR mRNA in hepatocytes induces cytoprotection by PTGES/LC3B activation of autophagy signaling. Similarly, cytotoxic immunological cascades are mitigated/prevented in HuR‐expressing macrophages when HO‐1 protein levels are stabilized.