A Review on Mechanisms of Action and Signaling Pathways of Natural Anti-hyperpigmentation Agents.

Hyperpigmentation is a dermatological condition characterized by excessive melanin production, resulting in skin darkening. Intrinsic and extrinsic mediators, including ultraviolet (UV) radiation, hormonal changes, inflammation, and genetic predisposition, contribute to hyperpigmentation pathogenesis. The current review thoroughly examines the biological processes involved in hyperpigmentation, with particular emphasis on its signaling pathways, particularly the cyclic adenosine monophosphate (cAMP), wingless-related integration site (Wnt)/β-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK), thereby providing mechanistic insights that may facilitate the development of effective treatments. The review also evaluates the safety, toxicity, and therapeutic efficacy of TYR inhibitors, arbutin, azelaic acid, ellagic acid, kojic acid, resveratrol, and the melanosome inhibitor niacinamide, for managing hyperpigmentation. Additionally, the review summarizes the in vitro and in vivo studies of these agents and other emerging plant extracts. Recent advances in the use of plant extracts for hyperpigmentation have shown promising efficacy; nevertheless, their translation into clinical and commercial applications remains limited. This limited translation might be attributed to the challenges related to standardization and the paucity of clinical evidence regarding long-term safety. Moreover, ongoing studies on natural anti-hyperpigmentation agents have highlighted the critical role of patent analyses in the advancement of biomedical research. This review provides a strategic direction for researchers to assess the safety, efficacy, and toxicity profiles of natural anti-hyperpigmentation agents.