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Abstract：
Fatty liver hemorrhagic syndrome (FLHS) in laying hens is a nutritional metabolic disease commonly observed in high-yielding laying hens. Sodium butyrate (NaB) and ferroptosis were reported to contribute to the pathogenesis of fatty liver-related diseases. However, the underlying mechanism of NaB in FLHS and whether it mediates ferroptosis remains unclear. A chicken primary hepatocyte induced by free fatty acids (FFAs, keeping the ratio of sodium oleate and sodium palmitate concentrations at 2:1) was established, which received treatments with NaB, the ferroptosis inducer RAS-selective lethal 3 (RSL3), and the inhibitor ferrostatin-1 (Fer-1). As a result, NaB increased biochemical and lipid metabolism indices, and the antioxidant level, while inhibiting intracellular ROS accumulation and the activation of the ferroptosis signaling pathway, as evidenced by a reduction in intracellular iron concentration, upregulated GPX4 and xCT expression, and inhibited NCOA4 and ACSL4 expression. Furthermore, treatment with Fer-1 reinforced the protective effects of NaB, while RSL3 reversed it by blocking the ROS/GPX4/ferroptosis pathway, leading to the accumulation of lipid droplets and oxidative stress. Collectively, our findings demonstrated that NaB protects hepatocytes by regulating the ROS/GPX4-mediated ferroptosis pathway, providing a new strategy and target for the treatment of FLHS.
摘要：
蛋鸡脂肪肝出血性综合征(FLHS)是高产蛋鸡常见的营养代谢性疾病。据报道，丁酸钠（NaB）和铁凋亡与脂肪肝相关疾病的发病机理有关。然而,NaB在FLHS中的潜在机制及其是否介导铁凋亡仍不清楚。游离脂肪酸诱导的鸡原代肝细胞(FFA，将油酸钠和棕榈酸钠浓度的比例保持在2:1)，接受了NaB治疗，铁凋亡诱导剂RAS选择性致死性3（RSL3），和抑制剂铁抑制素-1(Fer-1)。因此,NaB增加生化和脂质代谢指标，和抗氧化剂水平，同时抑制细胞内ROS积累和铁凋亡信号通路的激活，细胞内铁浓度的降低证明了这一点，上调GPX4和xCT表达，并抑制NCOA4和ACSL4的表达。此外，用Fer-1治疗增强了NaB的保护作用，而RSL3通过阻断ROS/GPX4/铁凋亡途径来逆转它，导致脂滴积累和氧化应激。总的来说，我们的发现表明，NaB通过调节ROS/GPX4介导的铁凋亡途径保护肝细胞，为FLHS的治疗提供了新的策略和目标。
