Work

ACAD8 deficiency promotes pathological cardiac hypertrophy in response to pressure overload by regulating histone isobutyrylation

Year: 2026

Type: article

Abstract: Branched-chain amino acids play critical roles in cardiac physiology and diseases. Genetic deficiency in the valine catabolic enzyme ACAD8 is clinically associated with isobutyryl-CoA deregulation and cardiomyopathy in humans, but its roles in cardiac disease remain undefined. Here, we show that the levels of ACAD8 are reduced in humans and male mice with cardiac hypertrophy. Cardiomyocyte-specific Acad8 knockout in male mice exacerbates cardiac hypertrophy and cardiac dysfunction underwent pressure overload. Mechanistically, Acad8 deficiency leads to the accumulation of its substrate isobutyryl-CoA, which enhances histone isobutyrylation, chromatin accessibility and TEAD2 enrichment at promoter regions of hypertrophy-related genes, which increases the sensitivity to hypertrophic stress in mouse hearts and cardiomyocytes. Conversely, ACAD8 overexpression in cardiomyocytes suppresses isobutyryl-CoA accumulation and histone isobutyrylation, thereby attenuating cardiac hypertrophy and dysfunction. These results elucidate the roles of ACAD8 deficiency in cardiac diseases and reveal histone isobutyrylation in transcription regulation and cardiac pathology.

Source: Nature Communications

DOI: 10.1038/s41467-026-72949-w