From Lactate to Lactylation: Novel Pathological Mechanisms and Potential Therapeutic Targets for High-Altitude Cerebral Edema

High altitude cerebral edema (HACE), a fatal terminal stage of acute mountain sickness (AMS), is triggered by rapid exposure to hypoxia at high altitudes.The pathophysiology of HACE is complex, involving multiple key processes including energy metabolism disorders, oxidative stress, blood-brain barrier (BBB) injury, and neuroinflammation, all of which interact to drive disease progression.Lactylation, a novel epigenetic regulatory mechanism discovered in 2019, provides a fresh perspective for HACE research.This mechanism regulates gene expression through the covalent binding of lactate to histones, and it also plays a crucial role in various conditions such as cancer and ischemichypoxic diseases.In HACE, hypoxia-driven glycolysis elevates lactate, promoting protein lactylation (e.g., NuRD complex in microglia, which is correlated with proinflammatory cytokines).Lactylation may regulate HIF-1/NF-B axis, inflammation, and metabolism in HACE pathogenesis.Currently, methods such as the inhibition of lactate dehydrogenase (LDH) /monocarboxylate transporters and the use of histone deacetylase inhibitors have been proven effective in regulating lactylation.However, the dual role of lactate in neuroprotection and neuroinjury under hypoxic conditions still requires further exploration.Future research should focus on deciphering the molecular networks related to HACE and developing precise intervention strategies to provide new directions for HACE treatment.