A working model linking oxidative stress, histone H3K18 lactylation and ALKBH3 in age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly and is driven primarily by retinal pigment epithelium (RPE) dysfunction. Although oxidative stress and mitochondrial dysfunction are well-established early events in AMD, how these bioenergetic deficits relate to chronic inflammation and neovascularization in advanced disease remains incompletely understood. This Hypothesis and Theory article focuses on an oxidative stress–lactate–epigenetic axis as a potential link. Oxidative damage can be followed by a Warburg-like glycolytic shift in experimental and some donor RPE systems, with intracellular lactate accumulation. Lactate can be converted to L-lactyl-CoA for histone lactylation; whether histone H3 lysine 18 lactylation (H3K18la) then promotes IL-6 or VEGFA transcription in human macular RPE is not established. Central to the framework is a proposed H3K18la–ALKBH3 feed-forward loop that would couple epitranscriptomic mRNA stabilization with epigenetic amplification. Emerging interventions aimed at this axis are discussed, including the peptide ghrelin. Ghrelin protects RPE in oxidative preclinical models and can activate AMPK in other systems; a sequence from ghrelin to reduced glycolysis, lactate and H3K18la in AMD RPE is a hypothesis, not an experimentally established AMD mechanism. Combinatorial strategies, such as pairing ALKBH3 inhibitors with metabolic modulators, are therefore hypothesis-generating approaches for earlier intervention.