Improving Non-Alcoholic Fatty Liver Disease Treatment in High-Fat Diet Fed Mice With Fisetin and Hydroxychloroquine: The Cooperative Pathways for Improved Metabolic Health Publisher Pubmed



Sattari M ; Panahi G ; Shahaboddin ME ; Sattari M ; Amiri S ; Taheri MA ; Karimpour A ; Amri J
Source: Current Medicinal Chemistry Published:2026

Abstract

Background: The high incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) as a hepatic component of metabolic syndrome is attributed to the ongoing rise in obesity rates. Given the beneficial effects of hydroxychloroquine (HCQ) on metabolism, there is growing interest in combining it with fisetin (FSN), a natural product, to treat NAFLD more effectively. Objective: The efficacy and safety of the combined therapy of FSN and HCQ in animal models of NAFLD were assessed, focusing on liver function, insulin sensitivity, oxidative stress, and inflammation. Materials and Methods: C57BL/6J mice were fed either a standard chow diet or a high-fat diet to induce NAFLD. FSN and HCQ were administered to the mice, and biochemical parameters related to glucose and lipid metabolism, as well as oxidative stress markers, were measured in serum and liver tissue. Analyses included Oil Red O staining, mRNA levels of key lipid metabolism molecules, and immunohistochemical assessments of macrophage infiltration. Statistical analyses were performed using GraphPad Prism 9. Results: While the HCQ group exhibited some improvements in certain markers, it also displayed adverse effects. The FSN group, particularly the FSN + HCQ group, effectively reversed insulin sensitivity, glucose homeostasis, and NAFLD markers by modulating lipid metabolism and inflammation pathways. HCQ exacerbated oxidative stress, which was mitigated by the effects of FSN. Conclusion: Despite concerns regarding the long-term side effects of HCQ, its combination with FSN presents a promising approach for improving the management of NAFLD by reducing risks and enhancing outcomes. © 2026, Bentham Science Publishers