SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury.

Sepsis is the leading cause of death in the intensive care unit and continues to lack effective treatment. It is widely accepted that HMGB1 is a key inflammatory mediator in the pathogenesis of sepsis. Moreover, some studies indicate that the functions of HMGB1 depend on its molecular localization and post-translational modifications. Our previous study confirms that SIRT1, a type III deacetylase, can ameliorate sepsis-associated acute kidney injury (SA-AKI). We explored the effect and mechanism of SIRT1 on HMGB1 using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and LPS-treated human kidney (HK-2) cell line. We found that HMGB1 is elevated in the serum but is gradually reduced in kidney cells in the later stages of septic mice. The acetylation modification of HMGB1 is a key process prior to its nucleus-to-cytoplasm translocation and extracellular secretion in kidney cells, accelerating the development of SA-AKI. Moreover, SIRT1 can physically interact with HMGB1 at the deacetylated lysine sites K28, K29, and K30, subsequently suppressing downstream inflammatory signaling. Thus, the SIRT1-HMGB1 signaling pathway is a crucial mechanism in the development of SA-AKI, and presents a novel experimental perspective for future SA-AKI research.