Physiological relevance of autocrine melatonin signaling in pineal and extrapineal sites: a systematic review

Beyond the pineal gland, melatonin is produced locally in many extrapineal organs, where it mediates local tissue homeostasis. However, little attention is paid to the physiological role of autocrine melatonin signaling across body organs. This study synthesizes original data to address this gap, as gaining insight into this topic could lead to new therapeutic approaches for diseases associated with melatonin. This systematic review used a narrative synthesis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline standards to synthesize original articles published between January 2000 and July 2025, using the Wiley Online Library and PubMed databases. From the 41 studies reviewed, various targets for the physiological relevance of autocrine melatonin signaling in pineal and extrapineal sites were noted. In descending order, the targets were immunoregulatory switch (8 studies), ovary and reproductive system (7 studies), pineal gland (6 studies), gut (5 studies), skin and hair follicles (3 studies), retina (3 studies), testes (3 studies), liver and metabolic tissues (2 studies), bone (2 studies), cardiovascular/endothelial compartment (1 study), and mitochondria (1 study). A layer of melatoninergic biology that is different from the traditional pineal endocrine signal and has biological and clinical significance is autocrine melatonin signaling in the pineal and numerous extrapineal locations. Although there is a translational potential, thorough mechanistic human research and better assays are required due to model heterogeneity and scarcity of human data.