Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis
Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration.
Authors
- Nidhi Shah (ORCID: https://orcid.org/0009-0003-5942-3454)
- Benjamin A. Yang (ORCID: https://orcid.org/0000-0001-7412-6261)
- Fanju W. Meng (ORCID: https://orcid.org/0000-0002-0119-4543)
- John O. Onukwufor (ORCID: https://orcid.org/0000-0003-4776-5003)
- Carlos A. Aguilar (ORCID: https://orcid.org/0000-0003-3830-0634)
- Patrick J. Murphy (ORCID: https://orcid.org/0000-0002-0880-392X)
- Sarah Hachmer
- Laura M. Calvi (ORCID: https://orcid.org/0000-0001-6969-239X)
- Gayatri Puri (ORCID: https://orcid.org/0000-0001-9310-0155)
- R. Blanc (ORCID: https://orcid.org/0000-0001-7069-4085)
- F. Jeffrey Dilworth (ORCID: https://orcid.org/0000-0002-6265-8102)
- Robert T. Dirksen (ORCID: https://orcid.org/0000-0002-3182-1755)
- Jeong-Hye Hwang (ORCID: https://orcid.org/0009-0005-3985-4657)
- Joe V. Chakkalakal (ORCID: https://orcid.org/0000-0002-8440-7312)
- Alireza Mousaei (ORCID: https://orcid.org/0000-0001-5717-961X)
- Noah Salama (ORCID: https://orcid.org/0000-0002-0918-3021)
- Elizabeth E Wacker
Institutions
- University of North Texas (US)
- University of Wisconsin–Madison (US)
- Duke University (US)
- Cornell University (US)
- University of Rochester Medical Center (US)
- BioSurfaces (United States) (US)
- University of Rochester (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-06-30
- DOI
- https://doi.org/10.1038/s43587-025-00902-5
- Citations
- 9
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 13.67
Funders
- University of Wisconsin-Madison
- National Institutes of Health
- Medical Center, University of Rochester