Mechanistic Insights into AKT1/GSK3β/CD36 Axis Regulation in ZLY06-Induced Hepatic Lipid Metabolism Dysfunction and Protective Intervention via AKT Activation Strategies

Xiaotong Cai; Yuqing Sun; Qin Zhang; Xiaoyun Liu; Ming Jin; Rongmi Zhang; Luyong Zhang; Zhenzhou Jiang

doi:10.1016/j.fct.2025.115628

Mechanistic Insights into AKT1/GSK3β/CD36 Axis Regulation in ZLY06-Induced Hepatic Lipid Metabolism Dysfunction and Protective Intervention via AKT Activation Strategies

Food Chem Toxicol. 2025 Jul 7:115628. doi: 10.1016/j.fct.2025.115628. Online ahead of print.

Authors

Xiaotong Cai¹, Yuqing Sun¹, Qin Zhang¹, Xiaoyun Liu¹, Ming Jin¹, Rongmi Zhang¹, Luyong Zhang², Zhenzhou Jiang³

Affiliations

¹ New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
² New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: lyzhang@cpu.edu.cn.
³ New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China; Animal Experimental Center, China Pharmaceutical University, Nanjing 210009, China. Electronic address: beaglejiang@cpu.edu.cn.

PMID: 40633829
DOI: 10.1016/j.fct.2025.115628

Abstract

The safety of compounds, particularly hepatotoxicity, is a critical focus in drug development. The novel PPARβ/γ dual agonist ZLY06, a candidate compound for the treatment of metabolic syndrome, exhibited significant hepatotoxic effects in animal studies, characterized by hepatic lipid accumulation and elevated liver enzyme levels. However, the mechanisms underlying ZLY06-induced hepatotoxicity remain unclear. This study investigated the AKT1/GSK3β/β-catenin/CD36 signaling axis to examine the role of the AKT signaling pathway in ZLY06-induced hepatic lipid accumulation. We found that ZLY06 inhibited AKT1 phosphorylation at Ser473, leading to the activation of GSK3β and β-catenin, which subsequently upregulated CD36 expression and promoted long-chain fatty acid uptake, thereby facilitating lipid accumulation. Experimental evidence demonstrated that AKT activators (such as SC79 and Recilisib) mitigated ZLY06-induced lipid accumulation by restoring AKT1 phosphorylation, reducing CD36 expression, and normalizing lipid metabolism. These findings provided critical mechanistic insights into ZLY06-induced hepatotoxicity and suggested a potential therapeutic strategy to alleviate hepatic lipid accumulation through AKT pathway activation. This work advances our understanding of drug-induced hepatic lipid metabolism disorders and lays a foundation for the development of safer therapeutic agents.

Keywords: AKT activation; AKT1 phosphorylation; CD36; GSK3β; ZLY06; hepatic lipid accumulation.