The role of necroptosis in non-alcoholic fatty liver disease-related carcinogenesis

Necroptosis is a highly immunogenic regulated cell death routine that depends on receptor-interacting protein 3 (RIP3) kinase activity. We aimed to evaluate the role of necroptosis in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)-driven carcinogenesis. C57BL/6 wild-type (WT) or RIP3-deficient (RIP3-/-) mice were fed a choline-deficient L-amino acid-defined diet (CDAA; n= 14) or an isocaloric control diet (CSAA; n= 14) diet for 66 weeks. RIP3 deficiency ameliorated CDAA-induced inflammation and fibrosis and decreased the NAFLD activity score. Intriguingly, RIP3-/- mice displayed increased body weight, as well as insulin resistance at 66 weeks. RIP3-/- mice tended to show reduced incidence of macroscopic preneoplasic nodules, accompanied by significantly reduced Ki67 positive hepatocytes. Microarray analysis and subsequent validation studies showed that absence of RIP3 hampered the expression of oncogenes and signaling pathways controlling tumour microenvironment and protected against oxidative stress. Overall, targeting RIP3-dependent signaling might be a promising approach to arrest NAFLD progression to HCC, although complementary approaches may be required to control insulin resistance in obese patients.