This dataset contains quantitative, bottom-up DIA proteomics data generated as part of a larger study entitled "AI-Guided CRISPR Screen Reveals Repurposed Drugs as Topical Psoriasis Therapeutics," and is organized into two complementary sub-studies. Sub-study 1 – Pharmacological Rescue in a Mouse Psoriasis Model The first proteomics component was designed to molecularly characterize pharmacological rescue effects in an imiquimod (IMQ)-induced mouse psoriasis model following prioritization of candidate targets from a CRISPR-based genetic screen. Mouse skin samples were collected from five experimental conditions: untreated control, IMQ only, IMQ plus the ALOX5 inhibitor zileuton, IMQ plus the OXTR antagonist cligosiban, and IMQ plus an IL-17RA blocking antibody serving as a positive control. Skin tissues were processed for bottom-up proteomics and analyzed using dia-PASEF on a timsTOF Ultra 2 mass spectrometer coupled to an Evosep One liquid chromatography system. Proteomic data were analyzed using DIA-NN in library-free mode against a SwissProt-reviewed Mus musculus reference proteome (Mouse_SwissProt_CanonicalAndIsoform_20250324.fasta). The resulting protein-level quantitative dataset enables assessment of molecular pathways associated with IMQ-driven inflammation and the extent to which these signatures are modulated or rescued by pharmacological intervention. Sub-study 2 – CRISPR Knockout Proteomics in Human Keratinocytes The second proteomics component was designed to characterize the proteomic consequences of genetically ablating the candidate therapeutic targets ALOX5 and OXTR in a human cellular psoriasis-relevant context. Human keratinocytes were subjected to CRISPR-mediated knockout of either ALOX5 or OXTR and compared against wild-type controls. Samples were processed for bottom-up proteomics and analyzed using dia-PASEF on a timsTOF Ultra 2 mass spectrometer coupled to an Evosep One liquid chromatography system. Proteomic data were analyzed using DIA-NN in library-free mode against a SwissProt-reviewed Homo sapiens reference proteome. The resulting dataset enables assessment of the downstream molecular signatures driven by loss of each target in human keratinocytes.