ABSTRACT 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.
Man et al. (Sun,) studied this question.