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Rutin Alleviates Oxidative Stress in Chicken Hepatocytes by Inhibiting Ribotoxic Stress Response
by
, , ,
Cangning Zhang
1,2
,
Tao Li
1,2,
Chengfeng Zhao
1,2,
Liqin Zhao
1,2,
Duniesky Rodriguez Acosta
3,
Osmany Chacon Chacon
3
,
Liumei Sun
1,2,
Weiguo Zhao
1,2,
Liang Qu
4 and
Manman Shen
1,2,* 1
Jiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, China
2
Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Scientific Research Center, Chinese Academy of Agricultural Sciences, Zhenjiang 212100, China
3
Protein and Bionatural Products Research Center, Ministry of Agriculture, Havana 999075, Cuba
4
Jiangsu Institute of Poultry Science, Yangzhou 225125, China
*
Author to whom correspondence should be addressed.
Animals 2026, 16(11), 1654; https://doi.org/10.3390/ani16111654
Submission received: 20 February 2026
/
Revised: 23 April 2026
/
Accepted: 27 May 2026
/
Published: 28 May 2026
(This article belongs to the Section Poultry)
Simple Summary
Oxidative stress in the liver is a major challenge in poultry production, often leading to compromised health and economic losses. This study investigated the ability of rutin, a natural plant compound, to protect chicken hepatocytes against oxidative damage. Using hepatocytes exposed to H2O2 to simulate physiological stress, we found that rutin pretreatment significantly enhanced the cells’ antioxidant defenses and reduced harmful lipid accumulation. We discovered that rutin achieves this by inhibiting a specific stress-response protein called ZAKα. When we overexpressed ZAKα in the hepatocytes, rutin’s protective effects were notably weakened. These results indicate that rutin effectively protects chicken hepatocytes by targeting ZAKα, suggesting it could be a valuable natural supplement to improve liver health and overall productivity in poultry flocks.
Abstract
Oxidative stress (OS) significantly impairs poultry production; however, the protective mechanisms of rutin in the chicken liver remain unclear. In this study, we investigated the regulatory effects of rutin on oxidative stress and lipid metabolism using H2O2-exposed primary hepatocytes derived from chicken embryos. Specifically, we focused on antioxidant indicators, the Nrf2/Keap1 signaling pathway, and the ZAKα-mediated ribotoxic stress response (RSR). Results showed that pretreatment with 800 μmol/L rutin significantly alleviated oxidative damage by increasing superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities, while decreasing malondialdehyde (MDA) and reactive oxygen species (ROS) levels. This protective effect was mediated by activation of the Nrf2/Keap1 signaling pathway and its downstream effectors, HO-1 and SOD2. Concurrently, rutin suppressed lipid accumulation, as evidenced by reduced levels of triglyceride (TG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C), along with the downregulation of SREBP1 expression. Mechanistically, we found that rutin inhibited ZAKα and its downstream signaling, the p38/JNK pathway, which is associated with RSR. Crucially, co-treatment with ZAKα overexpression significantly attenuated the protective effects of rutin on both antioxidant defense and lipid regulation, confirming that rutin functions by inhibiting ZAKα-mediated signaling to restore Nrf2 activity. Molecular docking revealed a binding energy of −8.6 kcal/mol between rutin and ZAKα, verifying that ZAKα serves as a potential target for rutin. Collectively, these findings elucidate a novel mechanism whereby rutin enhances antioxidant defense and inhibits lipid deposition via the ZAKα-p38/JNK-Nrf2 signaling pathway, providing a theoretical basis for the application of rutin as a targeted regulator in poultry health.
Keywords:
poultry; liver; rutin; oxidative stress; ribotoxic stress response
