storage is the major challenge that limits the scaling-up of this approach. Thus, screening for novel fungal isolates with reliable metabolic stability and sustainability for camptothecin production is the objective of this work. Among the recovered isolates, Aspergillus terreus (320 μg/l) and A. flavus (290 μg/l) “endophytes of Ficus elastica” were the most potent camptothecin producing isolates. The chemical identity of extracted camptothecin was resolved from the HPLC, NMR, FTIR and LC–MS analyses, with a strong antiproliferative activity against MCF7 (0.18 μM), LS174 T, HCT29 (0.29􀀀 0.43 μM), HEPG-2 (0.73 μM) cell lines. The yield of camptothecin was decreased by about > 60 % by the 7th subculturing for both fungal isolates. Upon using Blackett-Burman design to optimize their nutritional requirements by the fungal isolates, their yield of camptothecin were increased by approximately 2 folds, revealing the essentiality of some carbon, nitrogen and growth elicitors for biosynthesis of camptothecin. Interestingly, the biosynthetic machinery of camptothecin by the 7th generation fungal isolates were completely restored upon addition of 1% surface sterilized leaves of F. elastica, while all the other experimented plant extracts did not display any effect on camptothecin production. So, chemicals signals derived from the plant /or its entire microbiome “microbial communication” triggering the expression of camptothecin biosynthetic gene cluster of these fungi, could be the most conceivable hypothesis explaining the attenuation and restoration processes of camptothecin biosynthesis by target the fungal isolates. This is the first report describing the feasibility of A. terreus and A. flavus “endophytes of F. elastica” for camptothecin production with reliable metabolic and sustainable biosynthetic potency upon addition of the plant host’s entire microbiome, that could be a preliminary platform for scaling-up of camptothecin production.