European heart journal
October 10, 2026 · via Europe PMC
Palmitic acid promotes hypertrophic memory in cardiomyocytes via KDM5A/H3K4me3.
Yang K, Gao R, Shi J, +9 more, Sun A.
AI summary — for doctors, generated from the abstract only
In experimental work, a short palmitic acid exposure produced lasting pro-hypertrophic changes in heart cells through a KDM5A pathway.
What was studied
A UK Biobank analysis of 232,592 participants linking plasma saturated fats to heart failure, plus mouse and cell experiments using diets, pressure overload and cardiac Kdm5A-knockout mice.
Key findings
- High plasma saturated fatty acids were associated with greater heart failure risk in UK Biobank
- Short-term palmitic acid promoted hypertrophy and heart failure without further exposure
- Palmitic acid reduced KDM5A and raised H3K4me3, acting via MCT4
- The KDM5A agonist D18 improved the effect in mice
Clinical relevance
This preclinical work hints that dietary saturated fat may have persistent effects on the heart, but it is far from guiding care.
Who should care
Limitations
Mechanistic findings come from mice and cells, and the human data are observational associations.
This is hypothesis-generating biology, and any therapeutic relevance of KDM5A activation remains unproven in people.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
Background and aims
Palmitic acid (PA), the most abundant saturated fatty acid (SFA), is positively associated with heart failure (HF) risk. However, its role and mechanism underlying HF remain unclear. This study aimed to investigate the effects of a PA-enriched diet and potential therapeutic targets in HF.
Methods
The association between plasma SFAs and HF was investigated in a cohort of 232 592 UK Biobank participants. Mice were randomly categorized into three groups, where they were fed a PA-enriched, olive oil-enriched, or control diet for 4 weeks, followed by a 4-week dietary adaptation period on the control diet. A pressure overload model was established by transverse aortic constriction in these mice and cardiac-specific lysine demethylase 5A (Kdm5A)-knockout mice.
Results
The UK Biobank database revealed an association between high plasma SFA levels and increased HF risk. Our in vitro and in vivo results demonstrated that short-term PA treatment promoted cardiac hypertrophy and HF without further exposure to high levels of PA, indicating a pro-hypertrophic memory in cardiomyocytes. Mechanistically, PA promoted palmitoylation-driven KDM5A degradation via the ubiquitination pathway, thereby up-regulating histone 3 lysine 4 tri-methylation (H3K4me3). KDM5A/H3K4me3 promoted a pro-hypertrophic memory in cardiomyocytes, thus causing cardiac hypertrophy via a monocarboxylate transporter 4 (MCT4)-induced metabolic imbalance. Furthermore, KDM5A agonist D18 ameliorated this PA-mediated cardiac hypertrophy and HF.
Conclusions
A PA-enriched diet promotes pro-hypertrophic memory in cardiomyocytes, cardiac hypertrophy, and HF via KDM5A/H3K4me3/MCT4. The application of D18 may represent a promising therapeutic approach for PA-mediated cardiac hypertrophy and HF.
DOI
10.1093/eurheartj/ehag761
PMID
42855844
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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