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 Oct:204:115628. doi: 10.1016/j.fct.2025.115628.
Xiaotong Cai  1 ,  Yuqing Sun  1 ,  Qin Zhang  1 ,  Xiaoyun Liu  1 ,  Ming Jin  1 ,  Rongmi Zhang  1 ,  Luyong Zhang  2 ,  Zhenzhou Jiang  3
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: [email protected].
  • 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: [email protected].
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; Hepatic lipid accumulation; ZLY06.
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