Targeting Autophagy to Restore Intestinal Integrity in Sepsis: Resveratrol’s NOX1/SIRT1-Mediated Protective Effect

INTRODUCTION: A serious complication of sepsis that directly impacts patient outcomes is intestinal barrier disruption. Although the polyphenolic molecule resveratrol (RE) is well known for its anti-inflammatory and antioxidant properties, its specific role in targeting the NADPH oxidase 1 (NOX1)/sirtuin 1 (SIRT1) pathway to protect against sepsis-induced intestinal barrier failure remains unexplored. Therefore, this study aimed to comprehensively investigate this novel mechanism. METHODS: The lipopolysaccharide (LPS)-treated Caco-2 cells and sepsis mouse models (cecal ligation and puncture) were utilized to assess the protective effects of RE. Quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, histological analysis, immunohistochemistry, and Western blot were employed to examine inflammatory cytokine levels, autophagy markers, and intestinal barrier function. The roles of NOX1 and SIRT1 in RE-mediated protection were explored through NOX1 overexpression and related molecular analyses. RESULTS: RE significantly improved survival rates in sepsis mice, reduced inflammatory cytokines, and restored intestinal barrier function. RE reversed the increase of NOX1 and the decrease of SIRT1 in sepsis. Histological analysis data showed that RE protected the intestinal structure, maintained the expressions of tight junction proteins, and alleviated intestinal damage. In LPS-treated Caco-2 cells, RE inhibited inflammation, promoted autophagy, and suppressed reactive oxygen species production. NOX1 overexpression partially offset the protective effects of RE. CONCLUSION: By modifying the NOX1/SIRT1 signaling pathway, RE protects against sepsis-induced intestinal barrier failure. These results underline that the NOX1/SIRT1 pathway is instrumental in autophagy and inflammation control and that RE may be a viable treatment approach for sepsis-related intestinal damage.