Zinc Deficiency Induces Hepatic Oxidative Stress, Inflammation, and Programmed Cell Death in Mice

Zinc deficiency is closely related to oxidative stress, inflammation, and programmed cell death. In this study, mouse models with normal zinc (Con), zinc deficiency (L-Zn), and high zinc (H-Zn) and an in vitro model of AML-12 hepatocytes were established to systematically explore the effects of zinc deficiency on hepatic oxidative stress, inflammation, and programmed cell death. In vivo experiments showed that zinc deficiency significantly increased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in the liver (P < 0.05), inhibited the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and induced hepatocyte edema, inflammatory infiltration, and an increase in the number of TUNEL-positive apoptotic cells. Using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, it was found that zinc deficiency activated the NF-κB pathway (increased expression of p-IκB α and p-NF κB p65), significantly increased the expression of pro-inflammatory factors (TNF-α, IL-6, IL-1β, IL-18), and decreased the anti-inflammatory factor IL-10. In addition, zinc deficiency upregulated apoptosis-related genes (Cyt-C, Bax, Bcl-2, Caspase-3/9), necroptosis marker indicators (RIPK1, RIPK3, MLKL), and key molecules of pyroptosis (NLRP3, ASC, GSDMD, Caspase-1), indicating the programmed cell death is activated in a number of ways. In vitro experiments further verified the above experimental results. Flow cytometry showed that the apoptosis rate of AML-12 cells in the L-Zn group (17.20%) was significantly higher than that in the Con group (4.75%) and the H-Zn group (2.55%). The experiment concluded that zinc supplementation could effectively alleviate oxidative damage, inhibit the inflammatory pathway, and reduce the expression of programmed cell death-related factors. This study confirms that zinc deficiency activates programmed cell death through a multimodal pattern and provides a theoretical basis for studies related to zinc intake imbalance leading to liver injury.