1- Aspergillus fumigatus, endophytic isolate from Catharanthus roseus, was grown on different media in presence of various epigenetic modulators namely curcumin, valporic acid and SAHA. There was no significant effect on epothilone productivity by the fungus in response to these epigenetic modifiers, even by growing on the agro-industrial residues “lemon peels, orange peels, mandarin orange peel, kiwi peels, banana peels and cantaloupe peels” under submerged conditions. 2- The maximum yield of epothilone by A. fumigatus was obtained with orange peels (0.43 μg/g), followed by lemon peels (0.25 μg/g), mandarin orange peels (0.1 μg/g) under solid state fermentation. 3- The yield of epothilone by A. fumigatus was strongly increased by growing on orange peels with particle size 3 cm, moisture content 50% and inoculum size 105/ml 4- From the response surface methodology optimization bioprocess by placket-Burman design, the maximum actual and predicted yield of epothilone by A. fumigatus were 2.41μg/g and 2.4μg/g, grown on orange peels under solid state fermentation at run # 9. 5- From the metabolomics profiling of A. fumigatus grown on orange peels at solid state fermentation, approximately 68 metabolites were differentially fluctuated in the cultures of A. fumigatus grown in orange peels compared to control orange peels as substrate, as revealed from the ESI+ and ESI- modes. 6- From the chemical structural analysis of the extracted epothilone by LC MS/MS, the purified epothilone of A. fumigatus has a molecular mass of 517.2 m/z that mainly attributed to the methyl-epothilone, that being consistent with the molecular mass of un-methylated epothilone B which is 507.4m/z. 7- The purified A. fumigatus epothilone had a significant activity towards (IC50 0.98μg/ml), Pancl (IC50 1.5μg/ml), MCF7 (IC50 3.7μg/ml) and WI38 (IC50 4.6μg/ml), as well as a strong anti-tubulin polymerization activity (IC50 0.52μg/ml) compared to Paclitaxel (2.0μg/ml). 8- The effect of A. fumigatus epothilone on the immigration ability of HepG2 cells was assessed, the wound closure of the monolayer cells was estimated by ~63.7 and 72.5%, in response to the sample and doxorubicin, respectively, compared to negative control.