Protective effects of magnolol, an active compound of Houpu Sanwu Tang, on intestinal barrier function in sepsis: Mechanisms of PPARG activation and inhibition of JAK-STAT and NF-κB signaling.

Abstract

BACKGROUND: Sepsis, a dysregulated host response to infection, frequently leads to catastrophic intestinal barrier failure, a key driver of mortality. Magnolol, a bioactive compound from Magnolia officinalis, has shown pleiotropic therapeutic effects, but its role in sepsis-induced intestinal injury remains unclear. Here, we investigate the protective mechanisms of magnolol in sepsis, focusing on its modulation of inflammatory signaling. METHODS: We employed both in vitro (LPS-stimulated Caco-2 cells) and in vivo (cecal ligation and puncture model of sepsis) systems. The effects of magnolol on cellular viability, apoptosis, inflammatory cytokine production, and intestinal barrier integrity were assessed using a combination of molecular and histological techniques, including Western blot, immunofluorescence, ChIP, and Co-IP assays. RESULTS: Magnolol potently mitigated LPS- and sepsis-induced cellular damage, apoptosis, and inflammation, while preserving intestinal barrier function. Mechanistically, we identify magnolol as a direct transcriptional activator of peroxisome proliferator-activated receptor gamma (PPARG). Magnolol treatment robustly reversed the LPS-mediated suppression of PPARG transcriptional activity (P&#xa0;<&#xa0;0.001). This activation was crucial for its protective effects, as CRISPR-Cas9-mediated knockdown of PPARG abrogated magnolol's benefits. Furthermore, magnolol restored the physical interaction between PPARG and its co-activator p300/CBP, which was disrupted by LPS. Crucially, activation of PPARG by magnolol led to the dual inhibition of the pro-inflammatory JAK-STAT and NF-&#x3ba;B signaling pathways. CONCLUSION: Our study delineates a novel protective mechanism for magnolol in sepsis, demonstrating that it functions as a potent PPARG agonist to suppress the inflammatory cascade driven by the JAK-STAT and NF-&#x3ba;B pathways. These findings establish magnolol as a promising, mechanistically defined therapeutic candidate for treating sepsis-induced intestinal injury.