Abstract

Diabetic wound healing impairment, particularly diabetic foot ulcers (DFUs), is a prevalent and severe complication of diabetes mellitus, associated with high rates of amputation and substantial clinical burden worldwide. The sustained inflammatory response mediated by macrophages represents a core mechanism in this pathological process, with epigenetic dysregulation serving as a pivotal contributing factor. To investigate whether targeting the methionine cycle could restore epigenetic homeostasis, we focused on DZ2002, a potent and reversible S–adenosylhomocysteine hydrolase (SAHH) inhibitor that has shown anti–inflammatory efficacy in several immune–related disease models, including systemic sclerosis, psoriasis–like skin lesions, autoimmune encephalomyelitis, and dry eye disease. We established a db/db mouse diabetic wound model to evaluate its therapeutic efficacy. DZ2002 significantly accelerated wound closure and improved tissue repair, concomitant with a reduction in macrophage–driven inflammation. In vitro, DZ2002 potently suppressed macrophage activation and pro–inflammatory cytokine expression. Mechanistically, we explored the underlying epigenetic regulation and found that DZ2002 selectively downregulates the methyltransferase mixed lineage leukemia 1 (MLL1), thereby reversing the associated pathological increase in H3K4me3 and its enrichment at the promoters of inflammatory genes. The essential role of MLL1 in this process was confirmed, as its knockdown abolished the anti–inflammatory and epigenetic effects of DZ2002. Collectively, our findings demonstrate that DZ2002 effectively promotes diabetic wound healing by targeting the MLL1/H3K4me3 axis to resolve sustained macrophage inflammation. Moreover, this work validates SAHH as a critical upstream regulator of this pathogenic epigenetic pathway, offering a novel therapeutic strategy for chronic diabetic wounds.