Oxidative stress plays a central role in the pathogenesis of diabetes mellitus and its complications. Ficus exasperata has been widely used in traditional medicine for its potential antioxidant and antidiabetic properties. This study aimed to evaluate and compare the antioxidant and therapeutic effects of n-hexane and n-butanol leaf fractions of F. exasperata in sucrose-induced diabetic Drosophila melanogaster. Fractions were analyzed for total phenol and flavonoid content, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity. In vivo studies assessed survival rate, locomotor activity, glucose concentration, non-protein and total thiol levels, nitric oxide (NO), and hydrogen peroxide (H₂O₂) production. Gene expression analysis was carried out to determine the effects of both fractions on insulin-related genes (ILP-2, Imp-L2, and InR). The n-hexane fraction exhibited higher total phenolic content (152.12 ± 1.95 mg/g) and FRAP activity, whereas the n-butanol fraction showed superior DPPH radical scavenging (86.97 ± 0.92%) and α-amylase inhibition, leading to a greater reduction in glucose concentration. Both fractions enhanced thiol defense systems, reduced oxidative biomarkers (NO and H₂O₂), and improved locomotor activity in diabetic flies, with the n-butanol fraction showing the most pronounced effects. Gene expression analysis revealed dose-dependent upregulation of ILP-2, Imp-L2, and InR genes. The findings demonstrate that Ficus exasperata possesses significant antioxidant and antidiabetic activities, mediated through restoration of thiol defenses, reduction of oxidative stress, and modulation of insulin signaling genes. While the n-hexane fraction was richer in phenolic content, the n-butanol fraction exhibited superior antidiabetic potential, making it the recommended fraction for further therapeutic exploration. These results support the ethnomedicinal use of F. exasperata and highlight its promise as a natural therapeutic candidate for managing diabetes and oxidative stress-related complications.

 Keywords: Ficus exasperata, leaf fractions, oxidative stress, insulin signaling, Imp-L2, ILP-2, InR, Drosophila melanogaster, sucrose-induced diabetes.