Long non-coding RNA (lncRNA) FOXD3-AS1 expression is upregulated in lung cancer;however,its effect and mechanism on 5-fluorouracil (5-FU) resistance remain unclear.In this study,we deter-mined the effects of FOXD3-AS1-enriched exosomes derived from lung cancer cells on the prolifer-ation,invasion,and 5-FU resistance of lung cancer cells.Online bioinformatics database analysis showed that FOXD3-AS1 was upregulated in lung cancer progression.Real-time quantitative PCR results confirmed that FOXD3-AS1 expression was upregulated in lung cancer tissues and cell lines,and FOXD3-AS1 was greatly enriched in lung cancer cell-derived exosomes.ELAV-like RNA-binding protein 1 (ELAVL1) was identified as an RNA-binding protein of FOXD3-AS1.The lung cancer cell-derived exosomes promoted A549 cell proliferation and invasion and inhibited apoptosis caused by 5-FU,and transfection of si-FOXD3-AS1 or si-ELAVL1 in exosome-incubated A549 cells reversed these effects.Moreover,exosome-incubated A549 cells were co-transfected with si-FOXD3-AS1 and pcDNA-ELAVL1,showing the same cell proliferation,invasion,and 5-FU resistance as those of A549 cells treated with lung cancer cell-derived exosomes alone.Mechanistic studies identified that lung cancer cell-derived exosomes activated the PI3K/Akt pathway,and transfection of si-FOXD3-AS1 or treatment with the PI3K inhibitor LY294002 reversed the activation of the PI3K/Akt axis induced by exosomes.In conclusion,our study revealed that lung cancer cell-derived exoso-mal FOXD3-AS1 upregulated ELAVL1 expression and activated the PI3K/Akt pathway to promote lung cancer progression.Our findings provide a new strategy for lung cancer treatment.