In this study, we demonstrated that PHLPP2 is up regulated during APAP induced toxicity and promote apoptosis in SCH527123 by the inactivation of the Akt pathway leading to Nrf2 degradation via Gsk3β/Fyn kinase axis. Recent drug discoveries are targeting small molecules that inhibit PHLPP2 so as to enhance and understand the molecular mechanism and PHLPP2 action, which could provide a potential for its therapeutic application (Sierecki et al., 2010). Here, we selected Morin whose molecular intervention with PHLPP2 into PP2C domain has earlier been studied by our group where it has shown to bind PHLPP2 and reduce t-BHP evoked hepatotoxicity (Rizvi et al., 2015). Akt mediates survival mechanisms through phosphorylation of its substrate like Gsk3β and negatively regulates it. Suppressed Akt activation during stress, promotes cellular apoptosis by inhibiting Gsk3β phosphorylation. Several studies unveil the negative regulation of Fyn kinase, a member of the Src-A subfamily of tyrosine kinases, on Nrf2 stability and its nuclear retention. During oxidative injury, Fyn kinase has been demonstrated to translocate to the nucleus after being phosphorylated by Gsk3β at an unknown tyrosine residue and trigger Nrf2 export for degradation (Jain and Jaiswal, 2007).
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