Gut microbiota–derived indole-3-propionic acid alleviates endoplasmic reticulum stress by regulating FMO2 in MASLD

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global health challenge for which there are currently no approved drugs. Indole-3-propionic acid (IPA), as one of the primary metabolites of gut microbiota, can influence the development of liver diseases through the gut-liver axis, but how it contributes to liver diseases remains unclear. The present study was conducted to explore the possible molecular mechanisms of IPA in the development of MASLD. METHODS: Metabolomic analysis compared serum and fecal metabolite profiles between MASLD and normal mice. The effects of microbial metabolite IPA on MASLD were evaluated through the utilization of a mouse model and cell models. Transcriptome data analysis was used, and further validation was conducted through flow cytometry, western blotting, RNA interference, and immunoprecipitation. RESULTS: Serum and fecal IPA levels in high-fat diet-fed mice were significantly decreased compared with those of normal chow diet-fed mice. IPA supplementation reduced hepatic lipid accumulation and alleviated insulin resistance, liver damage, and steatosis development in high-fat diet-fed mice, while gut microbiota dysbiosis was restored. Mechanistic analysis suggested that IPA promoted FMO2 expression, enhancing the interaction between FMO2 and protein kinase R-like endoplasmic reticulum kinase (PERK) and inhibiting the PERK/eIF2α/ATF4/CHOP signaling cascade, then mitigating endoplasmic reticulum (ER) stress, such as reducing hepatocyte apoptosis and reactive oxygen species levels, ultimately improving MASLD. CONCLUSIONS: IPA can promote the expression of FMO2, which binds to PERK within the ER of hepatocytes. This binding process inhibits the phosphorylation of PERK, thereby affecting PERK-mediated ER stress, and subsequently leading to a reduction in hepatocyte apoptosis and oxidation. This study puts forward the IPA/FMO2/PERK axis as a potential therapeutic target in ER stress for MASLD.