Lysine　demethylase　5B　(KDM5B)　is　up-regulated　in　many　cancers,　including　breast　cancer.　However,　the　underlying　metabolic　mechanisms　of　KDM5B　on　breast　cancer　progression　are　poorly　understood.　Here,　we　showed　that　KDM5B　expression　positively　correlates　with　metastasis　in　breast　cancer.　Cell　functional　analyses　were　demonstrated　that　KDM5B　knockdown　and　KDM5B　inhibitor　AS-8351　inhibited　breast　cancer　cell　proliferation　and　migration.　Furthermore,　we　reported　that　KDM5B　knockdown　and　AS-8351　reversed　epithelial-mesenchymal　transition　(EMT)　and　decreased　the　protein　levels　of　fatty　acid　synthase　(FASN)　and　ATP　citrate　lyase　(ACLY)　in　MCF-7　and　MDA-MB-231　cells.　Interestingly,　we　found　that　activation　of　AMP-activated　protein　kinase　(AMPK)　signaling　pathway　is　involved　in　KDM5B-mediated　EMT　and　lipid　metabolism　reprogramming　in　breast　cancer　cells.　As　a　result,　silencing　of　KDM5B-induced　activation　of　AMPK　signaling　pathway　inhibited　breast　cancer　cell　proliferation　and　migration.　Taken　together,　our　findings　indicated　that　KDM5B　was　a　novel　regulator　of　lipid　metabolism　reprogramming,　and　it　was　suggested　a　new　strategy　to　treat　breast　cancer.