Protocatechuic aldehyde promotes diabetic wound healing by enhancing angiogenesis via H3K18 lactylation-mediated Acvr1c expression

Delayed wound recovery is a major health issue affecting people with diabetes. Histone lactylation is involved in tissue repair. However, it is not clear whether protocatechuic aldehyde (PCA) promotes diabetic wound healing through histone lactylation. In this study, a diabetic wound mouse model was constructed to delve into the role of PCA in vivo. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to determine genes affected by H3K18 lactylation (H3K18la) under PCA treatment. The effects and mechanisms of PCA on histone lactylation and angiogenesis were investigated through cellular experiments. We found that PCA accelerated wound healing and angiogenesis in diabetic mice, and significantly reduced the inflammatory response in wound tissues. Lactate and H3K18la levels were augmented in the model group in comparison with the control group, however, PCA treatment remarkably reversed their levels. ChIP-seq analysis revealed a significant enrichment of H3K18la at the Acvr1c locus, and this histone modification was downregulated by PCA treatment. PCA remarkably enhanced Acvr1c expression through H3K18la in HUVECs. Moreover, PCA treatment markedly elevated cell viability, migration and tube formation in comparison with the control group. However, this effect was counteracted by Acvr1c knockdown. In conclusion, PCA promoted HUVEC angiogenesis by increasing H3K18la-mediated Acvr1c expression, thereby promoting diabetic wound healing. This could offer a new treatment approach to enhance the effectiveness of healing diabetic wounds.