The Cutaneous Melatoninergic System: Endogenous Biology and Potential for Therapeutic Targeting

ABSTRACT Melatonin is best known as a pineal hormone that regulates circadian rhythms, but the skin also possesses an intrinsic melatoninergic system capable of local synthesis, metabolism and signalling. This system encompasses classical melatonin receptors, biologically active metabolites, non‐classical signalling pathways and receptor‐independent intracellular actions involved in cutaneous stress responses, with emerging evidence for broader roles in skin homeostasis. In this review, we integrate current mechanistic and clinical evidence on the cutaneous melatoninergic system and critically examine its therapeutic relevance. Human evidence is most consistent for the photoprotective effects of topical melatonin, whereas clinical data for photoaging, radiation dermatitis, wound healing, hair disorders, inflammatory dermatoses, pigmentary disorders and chronic pruritus remain limited or preliminary. Interpretation is further constrained by small sample sizes, heterogeneous formulations, short follow‐up and frequent use of combination products. Importantly, the clinical efficacy of exogenous melatonin and evidence that the endogenous cutaneous melatoninergic system represents a disease‐modifying therapeutic target are distinct questions. Establishing the therapeutic relevance of the endogenous system will require characterisation of disease‐associated alterations in local melatonin synthesis, metabolism and signalling, demonstration of molecular target engagement, and linkage to clinically meaningful outcomes.