SIRT3 deSUMOylation sustains hematopoietic stem cell activities under stressful conditions via the DHX58-IRF7 axis.

Hematopoietic stem cells (HSCs) sustain physiological hematopoiesis by generating all hematopoietic cells. However, the connection between HSC stemness/activities and organismal lifespan, especially under stress, remains incompletely understood. We previously revealed a unique mutation at the SUMOylation site of SIRT3 (lysine 223 to arginine, K223R) that could enhance its deacetylase activity. Here, using Sirt3-K223R transgenic mice, we demonstrate that SIRT3 deSUMOylation promotes HSC self-renewal, inhibits myeloid differentiation, and delays HSC senescence under multiple stress conditions. Notably, these effects are associated with extended lifespan in mice, though the underlying link between preserved HSC function and lifespan extension needs further investigation. Mechanistically, SIRT3 regulates mitochondrial metabolic activity and promotes the deacetylation of H3K9 and H3K27. This epigenetic modification attenuates the RIG-I signaling pathway by downregulating DHX58 and IRF7, sustaining HSC activities. Our study uncovers a unique SIRT3-DHX58-IRF7 axis that sustains HSC activities to delay organismal aging under stress, providing insights into potential anti-aging strategies targeting hematopoietic homeostasis.