Objective:To explore the effect and mechanism of miR-139-3p targeting secreted phosphoprotein 1(SPP1)on cis-diamminedichloroplatinum(DDP)in A549 lung cancer cells.Methods:A cisplatin(DDP)-resistant A549/DDP cell model was established via gradient concentration induction,validated by resistance index(IR=3.877)and IC50 determination.The re-sistant cells were divided into five groups:blank control,negative control,miR-139-3p mimic,SPP1 overexpression,and SPP1 knockdown.Multi-platform analyses were performed,including qPCR(miR-139-3p and SPP1 expression),Western blot(SPP1,p-AKT,and total AKT protein levels),CCK-8(proliferation and drug sensitivity),flow cytometry(apoptosis),and du-al-luciferase reporter assays(miR-139-3p/SPP1 interaction).Results:The cisplatin-resistant A549/DDP cells exhibited a signifi-cantly higher IC50 value compared to parental A549 cells(P<0.05),with a resistance index(IR)of 3.877.Quantitative PCR(qPCR)analysis revealed that miR-139-3p expression was markedly upregulated in the miR-139-3p mimic group versus the negative control group(P<0.05).Relative to the miR-139-3p mimic group,SPP1 mRNA levels were significantly elevated in the SPP1-overex-pression group and reduced in the SPP1-knockdown group(P<0.05).Western blotting confirmed corresponding changes in SPP1 pro-tein expression across these groups(P<0.05).CCK-8 assays demonstrated that miR-139-3p overexpression enhanced the proliferation inhibition rate and reduced the IC50 value compared to the negative control(P<0.05),whereas SPP1 overexpression reversed these effects,lowering the inhibition rate and increasing IC50(P<0.05).Compared with the miR-139-3p blank control,the luciferase activity of the wild-type SPP13'UTR luciferase reporter plasmid binding to miR-139-3p analog decreased(P<0.05),and the difference in the luciferase activity of the mutant SPP13'UTR luciferase reporter plasmid binding to miR-139-3p analog was not statistically significant(P>0.05).Compared with the negative control group,the protein expression level of p-AKT in miR-139-3p control group was signifi-cantly decreased(P<0.05),compared with the miR-139-3p control group and SPP1 knockdown group,the protein expression level of p-AKT in SPP1 overexpression group was significantly increased(P<0.05).Conclusion:Overexpression of miR-139-3p or knockdown of SPP1 could inhibit the proliferation of A549/DDP cells,enhance their sensitivity to cisplatin,and the mechanism may be related to the AKT signaling pathway.