Abstract: Background : Delayed fluid replacement after severe burns is a key clinical challenge that exacerbates intestinal barrier injury, but its molecular mechanism is not yet clear. The background of this study aims to explore the core role and regulatory mechanism of peroxisome proliferator activated receptor gamma (PPAR-γ) in this pathological process. Objective The aim of this study is to explore the key role and molecular mechanism of peroxisome proliferator activated receptor gamma (PPAR-γ) in delayed fluid replacement induced intestinal barrier injury after severe burns, in order to reveal its feasibility as a potential intervention target. Methods A mouse model of 30% TBSA third-degree burns was established using C57BL/6 mice, which were randomly divided into sham injury group, immediate resuscitation group, delayed resuscitation group (3h and 6h post-injury), and no resuscitation group to observe the effect of resuscitation timing on the intestinal barrier; another group was set up for delayed resuscitation + PPAR-γ agonist (rosiglitazone) or inhibitor (GW9662) intervention to verify its effect. The pathological damage of the small intestine, intestinal barrier permeability, tight junction protein, inflammatory factors, and PPAR-γ expression were detected. Results The degree of intestinal barrier injury (pathological score, elevated serum iFABP/DAO, downregulation of ZO-1/Occludin) and the expression of inflammatory factors were positively correlated with the delay in resuscitation time, accompanied by downregulation of PPAR-γ expression. Compared with the 6h delayed resuscitation group, activation of PPAR-γ significantly alleviated pathological damage, reduced permeability and inflammatory factors, and increased tight junction protein expression (P<0.05); inhibition of PPAR-γ aggravated the injury (P<0.05). Conclusion In the model of delayed fluid resuscitation after severe burns, the downregulation of PPAR-γ expression is a key factor in intestinal barrier injury, and its activation can partially reverse the damage, suggesting that the PPAR-γ pathway is a potential intervention target.