Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation-induced hepatic ischemia-reperfusion injury by regulating the AKT/GSK3β/NF-κB and AKT/mTOR pathways in rat Kupffer cells

Multiple mechanisms are involved in regulating hepatic ischemia-reperfusion injury (IRI), in which Kupffer cells (KCs), which are liver-resident macrophages, play critical roles by regulating inflammation and the immune response. Suberoylanilide hydroxamic acid (SAHA), a pan-histone deacetylase inhibitor, has anti-inflammatory effects and induces autophagy. To investigate whether SAHA ameliorates IRI and the mechanisms by which SAHA exerts its effects, an orthotopic liver transplantation (OLT) rat model was established after treatment with SAHA. The results showed that SAHA effectively ameliorated OLT-induced IRI by reducing M1 polarization of KCs through inhibition of the AKT/glycogen synthase kinase (GSK)3β/NF-κB signaling pathway. Furthermore, the present study found that SAHA upregulates autophagy 5 protein (ATG5)/LC3B in KCs through the AKT/mTOR signaling pathway and inhibition of autophagy by knockdown of ATG5 in KCs partly impaired the protective effect of SAHA on IR-injured liver. Therefore, the current study demonstrated that SAHA reduces M1 polarization of KCs by inhibiting the AKT/GSK3β/NF-κB pathway and upregulates autophagy in KCs through the AKT/mTOR signaling pathway, which both alleviate OLT-induced IRI. The present study revealed that SAHA may be a novel treatment for the amelioration of OLT-induced IRI.