Histone Lactylation Drives ALKBH5 to Worsen Cardiac Hypertrophy via ATF6 Demethylation

Cardiac hypertrophy, the thickening of heart muscle in response to stress, has now been linked to a chain of molecular events involving lactylation of histones, the RNA-demethylating enzyme ALKBH5, and the m6A modification of ATF6 messenger RNA. In a study published in Cell Biology and Toxicology, researchers used cell and animal models to map how this pathway aggravates hypertrophic growth of heart cells, offering what they describe as new insights into the regulatory mechanism of the condition.

The team worked with H9C2 cells, a rat heart-derived cell line, and induced hypertrophy-like changes by treating the cells with phenylephrine. Hypertrophy was assessed by α-actinin staining of cell surface area and by quantitative real-time polymerase chain reaction measuring hypertrophy marker genes. In the phenylephrine-treated cells, ALKBH5 expression rose. When the researchers knocked down ALKBH5, cell surface area shrank and hypertrophy marker levels fell in the induced cells, while normal, untreated H9C2 cells were unaffected, suggesting the enzyme’s role is tied to the hypertrophic state rather than baseline cell size.

The mechanistic core of the study concerns N6-methyladenosine, or m6A, a chemical modification of RNA. Using methylated RNA immunoprecipitation, dual-luciferase reporter assays, and actinomycin D treatment to block new transcription, the researchers showed that ALKBH5 removes m6A marks from ATF6 mRNA, thereby stabilising the transcript. When ALKBH5 was knocked down, demethylation of ATF6 was inhibited and its mRNA stability dropped. Conversely, overexpressing ATF6 abolished the reduction in cell surface area and marker levels caused by ALKBH5 knockdown, placing ATF6 downstream of ALKBH5 in the pathway.

The study also identified what drives ALKBH5 upregulation in the first place: histone 3 lysine 18 lactylation, or H3K18la, an epigenetic mark linking cellular lactate metabolism to gene expression. Western blotting and chromatin immunoprecipitation showed that H3K18la was enriched at the ALKBH5 promoter and promoted its transcription. Inhibiting MCT1, a lactate transporter, blocked both the H3K18la increase and the rise in ALKBH5, and an H3K18R mutation, which cannot be lactylated, abolished ALKBH5 transcription.

To test the pathway in a living organism, the researchers used a transverse aortic constriction model, in which pressure overload of the heart induces hypertrophy. Knockdown of ALKBH5 ameliorated the TAC-induced cardiac hypertrophy, and this protective effect was reversed when ATF6 was overexpressed, consistent with the in vitro findings. The authors conclude that H3K18 lactylation promotes ALKBH5 transcription, which facilitates m6A demethylation of ATF6, thereby aggravating cardiac hypertrophy. As the work relies on a cell line model and a single animal model of pressure overload, further studies will be needed to establish how the pathway operates in human heart disease, but the findings point to lactylation-dependent epigenetic control of RNA modification as a potential target in hypertrophic remodelling.

Subject of Research: The role of histone lactylation, ALKBH5 and m6A demethylation of ATF6 in cardiac hypertrophy

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

Article References: Yu, Z., An, P., Zhang, M., Wu, W., Qian, X., & Li, Y. (2026). Histone lactylation-mediated ALKBH5 regulates cardiac hypertrophy via m6A demethylation of ATF6. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-026-10310-z

Image Credits: AI Generated

DOI: 10.1007/s10565-026-10310-z

Keywords: cardiac hypertrophy, ALKBH5, ATF6, m6A methylation, histone lactylation, H3K18la, H9C2 cells, phenylephrine, transverse aortic constriction, MCT1, RNA demethylation, epigenetics