Inhibition of fatty acid-binding protein 4 alleviates psoriasis-like skin inflammation by modulating macrophage polarization.

Fatty acid-binding proteins (FABPs) are intracellular lipid chaperones that regulate gene expression by controlling lipid trafficking within subcellular organelles. Among them, FABP4 is primarily expressed in adipocytes and macrophages and has been implicated in inflammatory responses in adipose tissue; however, its role in skin inflammation remains poorly understood. Here, we investigated the immunomodulatory role of FABP4 using human psoriatic skin samples, single-cell RNA sequencing, and an imiquimod-induced mouse model of psoriasis. We further employed pharmacologic inhibition and genetic modulation of FABP4 to assess its effects on macrophage polarization, along with transcription factor regulon analyses to identify downstream regulatory mechanisms. FABP4 was highly expressed in macrophages infiltrating psoriatic skin, and in vivo pharmacological inhibition of FABP4 attenuated psoriasiform skin inflammation and shifted macrophage phenotypes, suppressing M1-associated features while promoting CD206-expressing alternatively activated macrophages. For mechanistic insights, we examined the regulon activity of transcription factors associated with macrophage polarization in psoriatic skin and identified an association between PPARG and macrophage polarization; our in vivo and in vitro experiments further demonstrated that FABP4 inhibition restored PPARG expression and activity in psoriasis mice, which was decreased by imiquimod application. Overall, our study demonstrated that FABP4 plays a critical role in skin inflammation by modulating macrophage polarization through PPARG regulation, suggesting that targeting FABP4 may represent a potential therapeutic strategy for psoriasis and other inflammatory skin diseases.