Huang Feifei, Wang Zhonghang, Zhou Mohan, Zhang Qian, Feng Jie
Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China.
Int J Mol Sci. 2025 May 22;26(11):4978. doi: 10.3390/ijms26114978.
Zinc (Zn) imbalance-deficiency or overload-is implicated in hepatocyte injury, yet its mechanisms and therapeutic strategies remain incompletely understood. This study investigated Zn dyshomeostasis-induced hepatotoxicity in AML12 hepatocytes and evaluated fisetin's protective potential in diet-induced Zn overload C57BL/6 mice for in vivo validation. In AML12 cells, both Zn deficiency and overload impaired hepatocyte viability and promoted oxidative stress, but only overload activated autophagy and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Fisetin, a natural flavonoid with well-documented antioxidant and anti-inflammatory properties, selectively mitigated Zn overload-induced AML12 cytotoxicity and oxidative damage by enhancing autophagic flux and Nrf2 signaling without Zn chelation, while demonstrating no effect on Zn deficiency. Specifically, fisetin required autophagy to sustain Nrf2 activation, as chloroquine abolished its protective effects. In vivo, fisetin administration (200 mg/kg BW, oral gavage) alleviated Zn overload-associated weight loss and hepatic oxidative damage in mice, paralleling its in vitro effects through reinforced autophagy-Nrf2 axis activation. The autophagy-dependent Nrf2 activation mechanism highlights fisetin's therapeutic potential for Zn-related liver disorders.
锌（Zn）失衡——缺乏或过量——与肝细胞损伤有关，但其机制和治疗策略仍未完全明确。本研究调查了锌稳态失调在AML12肝细胞中诱导的肝毒性，并评估了非瑟酮在饮食诱导的锌过载C57BL/6小鼠中的保护潜力，以进行体内验证。在AML12细胞中，锌缺乏和过量均损害肝细胞活力并促进氧化应激，但只有过量激活了自噬和核因子红细胞2相关因子2（Nrf2）途径。非瑟酮是一种具有充分文献记载的抗氧化和抗炎特性的天然黄酮类化合物，它通过增强自噬通量和Nrf2信号传导选择性减轻锌过载诱导的AML12细胞毒性和氧化损伤，而无需锌螯合，同时对锌缺乏无影响。具体而言，非瑟酮需要自噬来维持Nrf2激活，因为氯喹消除了其保护作用。在体内，给予非瑟酮（200mg/kg体重，口服灌胃）可减轻小鼠锌过载相关的体重减轻和肝脏氧化损伤，与其通过增强自噬-Nrf2轴激活的体外作用相似。自噬依赖性Nrf2激活机制突出了非瑟酮对锌相关肝脏疾病的治疗潜力。
