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Abstract

Itaconic acid improves ovarian dysfunction and follicular atresia in laying hens with fatty liver hemorrhage syndrome. • Itaconic acid alleviates endoplasmic reticulum stress and apoptosis via SERCA2-CaMK-FOXO1 signaling activation. • 4-Octyl itaconate protects granulosa cells from free fatty acid-induced apoptosis. • Targeting calcium homeostasis offers novel nutritional strategy for poultry metabolic reproductive disorders. Fatty liver hemorrhage syndrome (FLHS), a common nutritional metabolic disorder, exerts a significant impact on poultry egg production due to its detrimental effect on reproductive performance, while the underlying mechanism involving the ovaries remains unclear. Itaconic acid (IA), a metabolite discovered in the fungus, has garnered significant attention in therapeutic applications. This study aims to elucidate the pathological changes in the ovaries of hens with FLHS and to identify IA as a potential therapeutic agent for improving ovarian dysfunction in poultry. In vivo , a validated model of FLHS in laying hens, induced by a high-energy low-protein (HELP) diet, was established. IA supplementation improved egg production, egg quality, follicle number, and histological integrity of ovaries, while reducing serum and tissue markers of lipid peroxidation, Ca 2+ disorder, endoplasmic reticulum stress (ERS), and apoptosis. In vitro , given the poor cell membrane permeability of IA, 4-octyl itaconate (4-OI), a cell-permeable derivative that undergoes rapid intracellular hydrolysis to yield IA, was applied to ovarian granulosa cells challenged with free fatty acids (FFA). IA played a role in the restoration of sarcoplasmic reticulum/endoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2) expression, mitigating ERS and apoptosis. Importantly, inhibition of SERCA2 with thapsigargin (Tg) reversed the protective effects of IA, establishing SERCA2 as an essential mediator. These findings elucidated the mechanism by which IA alleviates FLHS-induced ovarian dy