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

Lactate promotes necroptosis through RIPK3 K63 lactylation, with PCAF-mediated modification enhancing kinase activity and membrane disruption in mice and humans.

• Why it matters: Understanding how metabolic changes influence cell death is crucial for developing therapies for diseases involving tissue injury and for improving athletic performance. The mechanisms linking lactate fluctuations to necroptosis remain unclear, limiting targeted interventions.
• What they did: The study used large-scale screening, genetic mutations, and pharmacological inhibition to show that lactate induces necroptosis via K63 lactylation of RIPK3, with PCAF as a key enzyme, in both pathological injury models and exercise conditions.
• The result: Findings demonstrate that blocking lactate-induced RIPK3 lactylation protects against tissue injury and that physiological lactate levels can activate necroptosis to promote muscle regeneration, suggesting new avenues for disease treatment and performance enhancement.