Mechanistic insights into AKT1/GSK3β/CD36 axis regulation in ZLY06-induced hepatic lipid metabolism dysfunction and protective intervention via AKT activation strategies

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.