Histone lactylation-mediated ALKBH5 regulates cardiac hypertrophy via m6A demethylation of ATF6

Cardiac hypertrophy is a complex physiological or pathological process. N6-methyladenosine (m6A) methylation has been reported to be involved in this process. This study aimed to investigate the effect of ALKBH5 on cardiac hypertrophy and the relevant molecular mechanisms using in vitro experiments. H9C2 cells were treated with phenylephrine (PE) to simulate hypertrophy, which was evaluated using α‐actinin staining and quantitative real-time polymerase chain reaction. m6A methylation of ATF6 mediated by ALKBH5 was evaluated by methylated RNA immunoprecipitation, dual-luciferase reporter analysis, and actinomycin D treatment. Histone 3 lysine 18 lactylation (H3K18la) was evaluated using western blotting and chromatin immunoprecipitation. The results showed that ALKBH5 expression was upregulated in PE-treated cells. Knockdown of ALKBH5 decreased cell surface area and reduced the levels of hypertrophy markers in PE-induced cells, but not affected these hypertrophic phenotypes in normal H9C2 cells. Furthermore, ALKBH5 knockdown inhibited m6A demethylation of ATF6 and thus reduced its mRNA stability. Overexpression of ATF6 abrogated the inhibition of cell surface area and marker levels induced by ALKBH5 knockdown. Additionally, H3K18la was enriched in the ALKBH5 promoter and promoted transcription. Moreover, MCT1 inhibition blocked H3K18la and ALKBH5 upregulation, and H3K18R mutation abolished ALKBH5 transcription. In vivo, ALKBH5 knockdown ameliorated TAC-induced cardiac hypertrophy, which was reversed by ATF6 overexpression. In conclusion, H3K18 lactylation promotes ALKBH5 transcription, which facilitates m6A demethylation of ATF6, thereby aggravating cardiac hypertrophy. The findings provide new insights into the regulatory mechanism of cardiac hypertrophy.