In this study, our results demonstrated that: (1) obesity subsequently impaired hepatic autophagy activity, which was mediated by HO-1/calpain 2 signaling; (2) this impairment of autophagy activity contributed to the greater vulnerability to I/R insult; and (3) IPC restored the calpain 2-impaired autophagy via induction of HO-1, thereby inhibited mitochondrial dysfunction and protected steatotic liver from I/R injury (Figure 8). The gene discussed is HMOX1; the disease is obesity due to melanocortin 4 receptor deficiency.