RIPK3 and heart failure: Mechanistically, loss of CSN8 is likely to activate the RIPK1-RIPK3 pathway to induce massive cardiomyocyte necroptosis, therefore contributing to heart failure.301,303 As such, treatment of the RIP1K inhibitor or deletion of even one allele of Ripk3 inhibited the death of cardiomyocytes and prolonged the lifespan of Csn8-deficient mice.304 Thus, a precise balance between neddylation and deneddylation is the key to maintain the normal heart physiology.257