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

TL;DR

This study uses spatial transcriptomics to uncover gene expression changes in acne, revealing new insights into lipid metabolism and retinoid signaling, and identifies potential new treatments.

Contribution

The study introduces a novel AP-1 inhibitor, T-5224, which reduces acne-like pustule formation in a mouse model.

Findings

Comedonal skin upregulates sebogenesis genes while pustular skin downregulates them.

Both acne subtypes show increased AP-1 transcription factors and elevated FABP5.

The AP-1 inhibitor T-5224 reduces pustule formation in a mouse model of folliculitis.

Abstract

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.

Our study characterizes gene expression changes that occur during acne pathogenesis. We also identify a novel therapeutic that reduces acne-like pustule formation in a mouse model of high fat diet-induced folliculitis.

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