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

Lactate-induced K63 lactylation of RIPK3 drives necroptosis, with 50% reduction in cell death observed in mouse models of injury and infection.

• Why it matters: Understanding how metabolic changes influence cell death is crucial for developing therapies for diseases involving tissue damage and inflammation.
• What they did: The study used large-scale screening, genetic mutations, and pharmacological inhibition to demonstrate that lactate promotes necroptosis via PCAF-mediated K63 lactylation of RIPK3, stabilizing the RIPK3-MLKL complex.
• The result: Blocking this pathway protected mice from myocardial injury and influenza, while exercise-induced lactate activated necroptosis to boost muscle repair and performance, revealing a key metabolic-death link.