Lactate couples metabolic state to necroptosis across pathological and physiological conditions.

Abstract

How fluctuations in central metabolites are transduced into cell-death decisions remains poorly understood. Here we show that lactate directly promotes necroptosis through lactylation of receptor-interacting protein kinase 3 (RIPK3) at lysine 63 (K63). Large-scale screening identified LDH inhibition as a suppressor of mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis, implicating intracellular lactate as a pivotal modulator. PCAF-mediated K63 lactylation enhances RIPK3 kinase activity and stabilizes the RIPK3-MLKL complex, driving membrane disruption. K63R mutation or PCAF loss potently suppresses necroptosis. This pathway operates in both pathological and physiological contexts: K63R knockin mice and LDH/PCAF inhibition protect against injury in myocardial ischemia-reperfusion and influenza A infection, whereas exercise-induced lactate engages the identical cascade to drive myofiber necroptosis, activating muscle stem cells and enhancing athletic performance. These findings reveal RIPK3-K63 lactylation as a pivotal mechanism linking lactate fluctuations to cell-death outcomes across disease and physiology.