Abstract
Abstract
Advances in molecular dermatology have deepened our understanding of acne pathogenesis. Yet, most available therapies focus on downstream inflammatory and microbial manifestations, whereas upstream sebocyte dysregulation, which drives disease initiation, persistence and relapse, remains a less direct therapeutic target. This review synthesizes current evidence on the molecular regulation of sebocyte biology and examines therapeutic implications of a sebocyte‐centred disease model. Key regulatory pathways are discussed, including peroxisome proliferator‐activated receptor‐γ (PPARγ)‐dependent transcriptional control, the FoxO1–mTORC1 nutrient‐sensing axis and GATA6‐mediated differentiation, alongside hormonal, genetic, microbial and environmental factors that influence sebocyte function. Single‐cell transcriptomic and spatial profiling studies are consistent with a proposed microdomain‐based model of the pilosebaceous unit that may help explain regional disease heterogeneity, variable therapeutic response and relapse. Established and emerging acne therapies are evaluated across four classical pathogenic domains: sebocyte dysregulation, follicular keratinization, microbial modulation and inflammation, showing that several non‐antibiotic strategies act across multiple pathogenic axes and may support antibiotic‐sparing approaches. Throughout, evidence is graded to separate established clinical evidence from translational, preclinical and hypothesis‐generating findings. The review links these mechanisms to practice, aligning with current guideline recommendations on limiting systemic antibiotic duration and on positioning hormonal therapy and newer topical agents. It aims to distinguish what is actionable now from sebocyte‐directed approaches that remain investigational and await phase III and comparative data. Because the sebocyte lies upstream of and integrates these domains, its modulation can, in principle, act across all four pathogenic pathways—the rationale for pathway‐inclusive, sebocyte‐directed agents and current interest in PPARγ modulation. Whether a single upstream agent can achieve the broad, durable disease control that now typically requires combination regimens remains to be established.