Recent studies indicate the metabolic oxidative stress, autophagy and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However the molecular mechanisms that link these important events in NASH remain unclear. In this study we investigated the mechanistic role of purinergic receptor X7 in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of LAMP2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression, chaperone-mediated autophagy markers LAMP2A and Hsc 70 but caused depletion of LC3B protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels as compared to wild type mice treated with BDCM. P2X7 receptor deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Further our findings presented here forms a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.