Work

Fisetin Attenuates Zinc Overload-Induced Hepatotoxicity in Mice via Autophagy-Dependent Nrf2 Activation

Year: 2025

Type: article

Abstract: 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.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms26114978

Authors: Feifei Huang, Zhonghang Wang, Mohan Zhou, Qian Zhang, Jie Feng

Institution: Zhejiang University

Language: English

Topic: Trace Elements in Health

Subfield: Nutrition and Dietetics

Field: Nursing

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499