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AbstractAcquired chemoresistance remains a significant challenge in the clinics as most of the treated cancers eventually emerge as hard-to-treat phenotypes. Therefore, identifying chemoresistance targets is highly warranted to manage the disease better. In this study, we employed a label-free LC-MS/MS-based quantitative proteomics analysis to identify potential targets and signaling pathways underlying acquired chemoresistance in a sub-cell line (A549DR) derived from the parental lung adenocarcinoma cells (A549) treated with gradually increasing doses of doxorubicin (DOX). Our proteomics analysis identified 146 upregulated and 129 downregulated targets in A549DR cells. The KEGG pathway and Gene ontology (GO) analysis of differentially expressed upregulated and downregulated proteins showed that most abundant upregulated pathways were related to metabolic pathways, cellular senescence, cell cycle, and p53 signaling. Meanwhile, the downregulated pathways were related to spliceosome, nucleotide metabolism, DNA replication, nucleotide excision repair, and nuclear-cytoplasmic transport. Further, STRING analysis of upregulated biological processes showed a protein-protein interaction (PPI) between CDK1, AKT2, SRC, STAT1, HDAC1, FDXR, FDX1, NPC1, ALDH2, GPx1, CDK4, and B2M, proteins. The identified proteins in this study might be the potential therapeutic targets for mitigating DOX resistance. [ABSTRACT FROM AUTHOR]