SUMMARYResearch backgroundFicus deltoidea(mistletoe fig) is a shrub well known among locals in Malaysia primarily for its treatment of toothaches, colds and wounds. The aim of this study is to determine the potential of leaves, sourced from three different varieties ofF. deltoidea, to exhibit antioxidant activity, a reduction of lipid concentration, and protein expression in steatosis-induced liver cell lines.Experimental approachThe leaves of threeF. deltoidea varieties, namelyFicus deltoideavar.angustifolia,Ficus deltoideavar.trengganuensisandFicus deltoideavar.kunstleri, were subjected to water extraction. The resulting crude extracts were fractionated using water and ethyl acetate. Palmitic acid was used to induce lipid accumulation (steatosis) in human liver (WRL68) cells, before all the samples were tested for their lipid-reducing activity. Several proteomic approaches were incorporated. The changes in protein expression were determined using 2-dimensional gel electrophoresis separation, whereas identification of our protein spots of interest was carried outviamatrix-assisted laser desorption/ionization time-of-flight.Results and conclusionsFicus deltoideavar.kunstlerialone demonstrated the ability to reduce lipids at the highest tested concentration (200 µg/mL) and was, therefore, used for subsequent experiments. Treatment withFicus deltoideavar.kunstleriwas found to restore redox status by increasing superoxide dismutase and glutathione peroxidase amounts and decreasing malondialdehyde formation. Six proteins were successfully identified; these were heat shock protein beta-1 (HSPB1), proteasome subunit alpha type 1 (PSMA1), glutathione S-transferase omega 1 (GSTO1), peroxiredoxin-1 (PRDX1), histone H2B (HIST1H2BD) and ubiquitin c-terminal hydrolase L3 (UCHL3). Through bioinformatics analysis, it was found that these proteins were significantly involved in specific pathways such as oxidative stress (PRDX1 and GSTO1), protein homeostasis (HSPB1) and degradation (UCHL3 and PSMA1).Novelty and scientific contributionF. deltoideapretreatment was shown to reduce lipid accumulation, thus improving the redox status and protein homeostasis. This suggests the role ofF. deltoideaas a preventive mechanism in non-alcohol fatty liver disease.