Enhancing Sirt1-mediated deacetylation of p62 with a self-assembling nanopeptide and resveratrol hydrogel to mitigate sepsis-induced inflammation

Abstract

Background: Sepsis-induced inflammatory damage remains a significant clinical challenge with limited effective treatments. Elucidating the molecular mechanisms that regulate macrophage function may reveal key therapeutic targets to combat sepsis.

Purpose: This study aimed to investigate the role of Sirtuin 1 (Sirt1) in regulating mitochondrial autophagy and immunometabolic remodeling in macrophages to alleviate inflammation associated with septic shock.

Study design: A controlled laboratory study was conducted using a murine sepsis model to elucidate the contribution of Sirt1 to macrophage function during sepsis-induced inflammation, employing both in vivo and in vitro approaches.

Methods: Sepsis was induced in mice via cecal ligation and puncture (CLP). Peritoneal macrophages (PMs) from sham-operated and septic mice were analyzed using single-cell RNA sequencing (scRNA-seq). Differential gene expression, immunostaining, transmission electron microscopy (TEM), and metabolomics were performed to evaluate the roles of Sirt1 and Sqstm1 (p62) in modulating macrophage autophagy and inflammation.

Results: Sirt1 expression was markedly reduced in PMs from septic mice. Sirt1-mediated deacetylation of p62 activated mitochondrial autophagy, suppressed lipopolysaccharide (LPS)-induced pro-inflammatory responses, and decreased mitochondrial reactive oxygen species (mtROS) production. Treatment with a self-assembling nanopeptide and resveratrol (Res) composite hydrogel improved survival rates and reduced tissue damage in septic mice. Integrated single-cell transcriptomics and metabolomics analyses demonstrated that Sirt1 modulated macrophage mitophagy and immunometabolic reprogramming, providing new insights into the molecular mechanisms of sepsis.

Conclusion: The self-assembling nanopeptide and Res hydrogel enhances Sirt1-mediated deacetylation of p62, promoting mitochondrial autophagy and immunometabolic remodeling, thereby mitigating sepsis-induced inflammation. This strategy represents a promising therapeutic approach for reducing inflammation-related damage in sepsis.

Keywords: Deacetylation; Resveratrol; Self-assembling nanopeptide; Sepsis; Sirtuin 1.