Potential role of druggable gene SLC15A2 in keratinocyte hyperproliferation in psoriasis.

Psoriasis is a chronic inflammatory skin disorder marked by abnormal keratinocyte proliferation and persistent immune activation. Identifying genetically supported druggable genes may offer new avenues for therapeutic development. We performed Mendelian randomization and colocalization analyses to identify druggable genes associated with psoriasis. These findings were then validated using an imiquimod-induced psoriasis-like mouse model, single-cell transcriptomics, and in vitro functional assays. SLC15A2 was identified as a gene potentially associated with psoriasis and was upregulated in psoriatic lesions. Single-cell analysis revealed that SLC15A2 was preferentially enriched in hyperproliferative keratinocyte subsets and correlated with cell-cycle activation and proliferation-related signaling pathways. Virtual knockout of SLC15A2 inhibited DNA replication and mitosis-related programs. In M5-stimulated HaCaT cells, knockdown of SLC15A2 decreased intracellular ROS levels and reduced keratinocyte proliferation and migration. Drug screening and molecular docking further indicated that SLC15A2 could be modulated by small molecules. Overall, these results suggest that SLC15A2 is a potential pathogenic gene with therapeutic relevance in psoriasis, providing insights into its role in keratinocyte hyperproliferation.