Ferroptosis in bovine mastitis: multidimensional mechanisms, stratified assessment, and intervention prospects

Mastitis remains a major constraint on dairy cow health and production efficiency. Even after pathogen clearance, inflammation, epithelial injury, and lactation impairment can persist, indicating that disease outcome is not determined solely by pathogen burden. Ferroptosis, a regulated form of cell death driven by iron-dependent membrane phospholipid peroxidation, provides a mechanistic framework that links iron dyshomeostasis, oxidative injury, and irreversible tissue damage. Current evidence suggests that increased oxidative load, altered iron flux, restriction of the cysteine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, and remodeling of the membrane-lipid substrate pool can jointly lower the ferroptotic threshold of mammary epithelial cells in the mastitic microenvironment. Within defined pathogen contexts and temporal windows, oxidized lipids and damage-associated molecular patterns (DAMPs) may further contribute to inflammatory amplification, blood-milk barrier disruption, and lactation decline. However, direct in vivo causal evidence in bovine mastitis remains limited. Ferroptosis further intersects with pyroptosis, necroptosis, and other regulated cell-death pathways, underscoring its strong context dependence. This review synthesizes current evidence on the core mechanisms of ferroptosis, its triggers in the mastitic microenvironment, the translation of molecular injury into tissue dysfunction, evidence standards for causal attribution, boundaries of contribution, and prospects for stratified assessment and intervention. In sum, ferroptosis is best regarded as a candidate framework for host-damage amplification in mastitis rather than a universally established execution pathway. Advancing its translational value will require spatiotemporally resolved evidence, cell-type specificity, and causal rescue experiments.