The Role of Flavonoids in Alleviating Mammary Gland Inflammation: A Review.

Mammary gland inflammation, clinically expressed as mastitis in dairy ruminants and lactating women, arises from a self-amplifying loop of pathogen sensing, oxidative stress and innate immune activation, and remains a leading driver of antibiotic use, milk-quality loss and morbidity. Mounting pressure to reduce antimicrobial dependence has refocused attention on flavonoids-structurally diverse plant polyphenols with multi-target bioactivity, derived mainly from in vitro and rodent mastitis models. This review integrates contemporary evidence on the six principal flavonoid subclasses within a unifying molecular framework. Across subclasses, flavonoids converge on shared targets: the TLR4-MyD88-NF-κB axis, MAPK cascades, the Keap1-Nrf2-ARE antioxidant pathway, the NLRP3 inflammasome and tight-junction proteins of the blood-milk barrier. Less canonical mechanisms-m6A epitranscriptomic regulation, ferroptosis suppression, AhR signalling, anti-virulence binding to bacterial enzymes such as IGPD, and gut-microbiota-driven remodelling of the gut-mammary axis-expand the pharmacological landscape. We additionally appraise the subclasses comparatively, identifying flavanones and the flavone baicalin as carrying the strongest translational evidence, and examine the conflicting findings, model limitations, and delivery, residue and regulatory barriers that currently separate mechanistic promise from on-farm application. We outline structure-activity considerations and translational priorities, and position flavonoids as mechanism-rich, antibiotic-sparing candidates for the prevention and adjunctive management of mammary gland inflammation in dairy ruminants.