Exploring the Comedone Switch through Single-Cell Resolution of Human Acne Lesions

Acne vulgaris is one of the most prevalent inflammatory skin diseases worldwide, yet the molecular events initiating comedogenesis remain poorly understood. The comedone switch hypothesis proposes that acne originates from an imbalance in lineage commitment within the junctional zone of the pilosebaceous unit, promoting infundibular differentiation at the expense of sebaceous gland maintenance. However, direct evidence from human acne tissue at single-cell resolution has been lacking. Here, we integrated single-cell transcriptomic datasets from healthy skin, nonlesional skin of acne patients, and lesional acne tissue to investigate early transcriptional changes associated with comedogenesis. We identified a previously uncharacterized cell population in nonlesional skin with transcriptomic features suggestive of a microcomedone-like state and mapped this population across independent datasets to characterize its relationship to comedonal keratinocytes. Comedonal remodeling was characterized by enhanced keratinization and inflammatory programs. Quantitative analyses supported a shift from sebaceous toward infundibular cell fate, providing data-driven support for the comedone switch hypothesis in human acne. Beyond the pilosebaceous unit, we identified broader epithelial alterations, including loss of POSTN and ERRFI1 expression in basal interfollicular epidermal keratinocytes. Together, these findings provide a cell-resolved view of transcriptional changes associated with human comedogenesis and highlight candidate pathways that may contribute to lineage imbalance within the upper hair follicle.