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

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-07-02 DOI:10.1016/j.phymed.2025.157047

Baoquan Wang , Ying Wang , Zhansheng Hu , Shuang Peng , Na Li , Zhang Dan , Haiyan Fu , Huiping Wu

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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.

Abstract Image

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利用自组装纳米肽和白藜芦醇水凝胶增强sirt1介导的p62去乙酰化以减轻败血症诱导的炎症

脓毒症引起的炎症损伤仍然是一个重大的临床挑战，有效的治疗方法有限。阐明调节巨噬细胞功能的分子机制可能揭示对抗败血症的关键治疗靶点。目的探讨Sirtuin 1 （Sirt1）调节巨噬细胞线粒体自噬和免疫代谢重塑，减轻脓毒性休克相关炎症的作用。研究设计采用体内和体外两种方法，利用小鼠脓毒症模型进行对照实验室研究，阐明Sirt1在脓毒症诱导炎症期间对巨噬细胞功能的贡献。方法采用盲肠结扎穿刺法（CLP）诱导小鼠脓毒症。采用单细胞RNA测序（scRNA-seq）分析假手术小鼠和脓毒症小鼠的腹膜巨噬细胞（pm）。通过差异基因表达、免疫染色、透射电镜（TEM）和代谢组学来评估Sirt1和Sqstm1 （p62）在调节巨噬细胞自噬和炎症中的作用。结果sirt1在脓毒症小鼠PMs中的表达明显降低。sirt1介导的p62去乙酰化激活了线粒体自噬，抑制了脂多糖（LPS）诱导的促炎反应，并降低了线粒体活性氧（mtROS）的产生。用自组装纳米肽和白藜芦醇（Res）复合水凝胶治疗可提高脓毒症小鼠的存活率并减少组织损伤。综合单细胞转录组学和代谢组学分析表明Sirt1调节巨噬细胞有丝分裂和免疫代谢重编程，为脓毒症的分子机制提供了新的见解。结论自组装纳米肽和Res水凝胶增强sirt1介导的p62去乙酰化，促进线粒体自噬和免疫代谢重塑，从而减轻败血症诱导的炎症。这种策略代表了一种有希望的治疗方法，可以减少败血症中炎症相关的损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.