The principal findings are: (1) Elevated expression of Caspase 6 correlates with severe liver histopathology and functional injury in patients undergoing hepatectomy; (2) Caspase 6 deficiency reduces liver inflammation, oxidative stress and iron overload in ischemic livers; (3) Caspase 6 deficiency promotes NEMO-mediated phosphorylation of IκBα, causing p-IκBα to bind to RIPK1 and the subsequent RIPK1 degradation; (4) RIPK1-mediated ASK1 phosphorylation results in increased NEK7/NLRP3-driven liver inflammation and HMGB1-induced ferroptosis. The gene discussed is CASP6; the disease is inflammation.