ArticleCell death & disease2023
Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity.
Article in Cell death & disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 13 citations in OpenAlex.
- Ferroptosis in musculoskeletal disorders: Emerging mechanisms and therapeutic opportunities (Review).International journal of molecular medicine · 2026Review
- An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer.Nature communications · 2026Article
- Regulation of apoptosis, ferroptosis, and pyroptosis mediated by acetylation.Cell death discovery · 2026Review
- Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy.Nature aging · 2025Article
- The N-terminal fragment of histone deacetylase 4 (1-669aa) promotes chondrocyte apoptosis via the p53-dependent endoplasmic reticulum stress pathway.Journal of cellular and molecular medicine · 2024Article
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Authors and funding
16 authors at 6 institutions in 1 country.
Funding
Abstract
Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.
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Registered trials
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