Mechanisms of Autophagy and Inflammatory Response Crosstalk in Sepsis-Associated Intestinal Dysfunction

Sepsis-associated intestinal dysfunction (SAID) drives multiorgan failure through dysregulated autophagy-inflammation crosstalk, for which effective therapies remain limited. This review systematically delineates SAID pathophysiology, evaluates preclinical and clinical evidence for autophagy-targeted interventions, and explores emerging intestinal-specific therapeutic targets. Autophagy preserves intestinal barrier integrity by clearing damaged organelles and suppressing NLRP3 inflammasome activation, whereas inflammatory mediators such as TNF-α/IL-6 and reactive oxygen species impair autophagic flux via Beclin-1 destabilization and lysosomal dysfunction, establishing a pathogenic vicious cycle. Preclinical evidence demonstrates that rapamycin and TFEB agonists enhance autophagy, while ATG5 overexpression and NLRP3 siRNA restore epithelial homeostasis. Clinically, IL-1 receptor antagonists have demonstrated efficacy in specific sepsis subpopulations. Stage-specific therapeutic optimization is essential, as interventions must be tailored to the hyperinflammatory versus immunoparalysis phases. Novel intestinal-barrier-specific targets-including aquaporin-3 (AQP3), ghrelin, and Nur77-emerge as key regulators of the autophagy-inflammation axis and represent promising therapeutic candidates. Targeting autophagy-inflammation crosstalk holds significant therapeutic potential, though clinical translation requires human-relevant models and precision medicine approaches to address disease heterogeneity and stage-specific pathophysiology.