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Cytarabine-based chemotherapy is the primary treatment. However, drug resistance presents a significant challenge leading to treatment failure. Our study explores the underlying correlation between AML stiffness and its drug resistance feature. We employed microfluidic technology to measure AML cell deformability, demonstrating that drug-resistant cells exhibit increased stiffness compared to their drug-sensitive counterparts. Transcriptomic analysis revealed that enhanced stiffness in drug-resistant cells is associated with upregulated cytoskeletal protein expression and increased lipid metabolism, particularly the peroxisome proliferators-activated receptor (PPAR) signaling pathway. Mechanistically, we found that knocking down PLIN2 at the genetic level and increasing the cholesterol level promoted the deformation of drug-resistant cells, indicating that intracellular lipid levels are involved in the regulation of cell softness. 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