# Fisetin alleviates lipopolysaccharide-induced mastitis by inhibiting ferroptosis and modulating the gut microbiota

## TL;DR

Fisetin, a natural compound, reduces inflammation in bovine mastitis by targeting oxidative stress and gut microbiota changes.

## Contribution

This study reveals fisetin's novel role in alleviating mastitis through ferroptosis inhibition and gut microbiota modulation.

## Key findings

- Fisetin reduces inflammatory cytokines in LPS-induced mastitis models.
- Fisetin increases short-chain fatty acids, aiding in blood-milk barrier restoration.
- Fisetin alters gut microbiota and metabolites in mastitis-affected mice.

## Abstract

Bovine mastitis poses an enormous challenge to the dairy industry. At present, dependence on antibiotic therapy has led to problems such as antibiotic-resistant bacteria and drug residues. Therefore, it is very important to seek alternative therapies for the treatment of bovine mastitis. Fisetin (FIS) with antioxidant and anti-inflammatory properties is found in various fruits and vegetables, although its regulatory role in mastitis treatment remains unclear. In the present study, we employed lipopolysaccharide (LPS)-induced cellular and animal mastitis models to investigate the regulatory effects of FIS on oxidative stress and ferroptosis pathways in mastitis treatment, utilizing techniques such as western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence, hematoxylin-eosin (HE) staining, ROS, MDA, SOD, T-AOC, tissue total iron content analysis, mouse gut microbiota sequencing, and untargeted metabolomics. The results demonstrated that FIS modulates oxidative stress and ferroptosis pathways, leading to a reduction in intracellular and mouse mammary tissue inflammatory cytokines level. Furthermore, FIS treatment altered the gut microbiota structure and metabolites in LPS-induced mice, increasing short-chain fatty acid (SCFA) levels, which contributed to the restoration of the blood-milk barrier and alleviation of mastitis. This study could lead to novel therapeutic strategies for bovine mastitis based on traditional Chinese medicine.