Spatial transcriptomics identifies differentiation, lipid metabolism, and retinoid pathway alterations in acne vulgaris.

Acne vulgaris is a common skin condition involving complex interactions among lipid-secreting sebaceous glands, keratinocytes, immune cells, and microbiota. While retinoids are effective for treating acne, disease pathogenesis remains poorly understood. In particular, it remains unclear how different subtypes of acne, including inflammatory (pustular) and noninflammatory (comedonal) lesions, vary in gene expression, signaling, and sebaceous gland involvement. Here, we performed spatial transcriptomics on healthy, nonlesional, comedonal, and pustular acne skin using a custom panel targeting sebaceous differentiation, lipid metabolism, and retinoid signaling pathways. We also designed a specialized segmentation pipeline to improve transcript assignment in the spatially complex sebaceous gland. Our analyses identified a PPARG+ transitional basal cell state in sebocytes and revealed that comedonal skin upregulates sebogenesis genes, whereas pustular skin downregulates sebogenesis. Both lesion types exhibited increased AP-1 transcription factors and elevated FABP5, a chaperone that blunts retinoic acid receptor signaling. Finally, we demonstrated that an AP-1 inhibitor, T-5224, downregulates FABP5 in human keratinocytes and reduces pustule formation in a mouse model of high-fat diet-induced folliculitis. Altogether, these findings indicate that altered lipogenesis, retinoid signaling, and keratinocyte differentiation are key features of acne, and nominate AP-1 and FABP5 as potential therapeutic targets.