Sebocyte Dysfunction in Skin Health and Disease: Physiological Regulation, Pharmacological Modulation, and Therapeutic Targeting.

BACKGROUND: Sebaceous glands and their specialized lipid-producing cells, sebocytes, are essential for maintaining skin homeostasis through sebum production, barrier support, and immune regulation. Dysregulated sebocyte activity contributes to common inflammatory skin disorders, particularly acne vulgaris and seborrheic dermatitis. Although many studies have examined individual regulators of sebocyte function, current knowledge remains fragmented across metabolic, hormonal, inflammatory, microbial, and environmental pathways. SUMMARY: This review provides a pathway-centered overview of sebocyte biology, with emphasis on the physiological and pharmacological mechanisms that regulate lipid metabolism, differentiation, proliferation, and inflammatory responses. Intrinsic signals, including androgens, insulin-like growth factor 1, epidermal growth factor, vitamin D, and stress-related mediators, interact with extrinsic factors such as microbial stimuli, hypoxia, radiation, and chemical exposures. These diverse inputs converge on recurrent regulatory hubs, including PI3K/Akt/mTOR, AMPK/SIRT1, TLR/NF-κB, AhR, and inflammasome-associated pathways. This review further discusses how therapeutic agents and bioactive compounds modulate these networks through shared control points that coordinate sebogenesis, inflammation, and sebocyte differentiation. Although sebocyte-based models provide valuable mechanistic insight into pathway-level regulation, further validation in physiologically complex and clinically relevant systems remains important. KEY MESSAGES: Sebocytes should be viewed not only as lipid-producing cells but also as immunometabolic regulators of the skin microenvironment. A pathway-centric framework helps connect diverse upstream stimuli with a limited number of disease-relevant functional outcomes. Targeting shared regulatory hubs, rather than single downstream effectors, may provide a more rational basis for developing therapeutic strategies for sebaceous gland-associated disorders.