Propyl gallate mitigates diabetic liver injury via suppressing SLC7A11/GPX4-mediated hepatic ferroptosis and modulating gut-liver axis

Hepatic glycolipid metabolic dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), with emerging evidence implicating ferroptosis as a critical pathogenic mechanism. Propyl gallate (PG), a naturally occurring antioxidant, may counteract redox imbalance; however, its impact on ferroptosis and gut-liver axis remains poorly understood. In this study, we investigated the protective effects of PG against high-fat diet (HFD)-induced diabetic liver injury in both in vivo and in vitro models. A combination of hepatic metabolomics, ferroptosis-related assays, and 16S rRNA sequencing was employed. PG significantly reduced hepatic lipid accumulation and oxidative stress by inhibiting ferroptosis, primarily through activation of the SLC7A11/GPX4 axis. Metabolomic analysis further demonstrated PG-mediated normalization of lipid peroxidation and glutathione metabolism in the liver. Notably, PG also enhanced intestinal barrier integrity by upregulating tight junction proteins (e.g., occludin, and ZO-1) and reshaping gut microbial composition, marked by increased abundance of beneficial genera such as Lactobacillus and Ruminococcus, known for their anti-inflammatory and antioxidant roles. Collectively, these findings suggest that PG ameliorates diabetic liver injury via dual mechanisms: (1) direct inhibition of SLC7A11/GPX4-dependent ferroptosis and (2) indirect modulation of gut microbiota to preserve intestinal barrier function. This study positions PG as a promising candidate for T2DM therapy by targeting both hepatic redox imbalance and gut dysbiosis.