This project contains DIA-based quantitative proteomics data generated from cultured HCT116 colorectal cancer cells treated with DMSO or LZ-A4. Proteomic profiling was performed on an Orbitrap Astral mass spectrometry platform to characterize global protein expression changes associated with pharmacologic depletion of legumain, with a particular focus on mitochondrial ribosomal proteins, oxidative phosphorylation components, and mitochondrial stress-related pathways in colorectal cancer cells.