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.