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Mechanisms

Non-canonical roles of Keap1/Nrf2 in regulating quiescence and early activation in adult muscle stem cells

Nature Communications

Abstract

This study reveals Keap1 regulates muscle satellite cell quiescence by promoting Nrf2 degradation. In Keap1-null MuSCs, Nrf2 reaches intermediate levels via GSK3β-dependent degradation. In female mice, estrogen-mediated GSK3β inactivation elevates Nrf2 to peak levels, causing spontaneous quiescence exit.

Key Findings

  • KEAP1/NRF2 has non-canonical roles beyond antioxidant defense
  • KEAP1 loss impairs muscle stem cell quiescence in sex-specific manner
  • First demonstration of sex-dependent KEAP1/NRF2 regulation
  • Implications for regenerative medicine and sarcopenia

Clinical Significance

Reveals entirely new NRF2 functions in stem cell biology. May lead to NRF2-targeted approaches in regenerative medicine.

Citation

Non-canonical roles of Keap1/Nrf2 in muscle stem cells. (2025). Nature Communications.

DOI: 10.1038/s41467-025-65506-4