Research on new ingredients that can prevent excessive melanin production in the skin while considering efficacy, safety but also environmental impact is of great importance to significantly improve the profile of existing actives on the market and avoid undesirable side effects. Here, the discovery of an innovative technology for the management of hyperpigmentation is described. High‐throughput screening tests on a wide chemical diversity of molecules and in silico predictive methodologies were essential to design an original thiopyridinone backbone and select 2‐mercaptonicotinoyl glycine (2‐MNG) as exhibiting the most favorable balance between the impact on water footprint, skin penetration potential and performance. The effectiveness of 2‐MNG was confirmed by topical application on pigmented reconstructed epidermis and human skin explants. In addition, experiments have shown that unlike most melanogenesis inhibitors on the market, this molecule is not a tyrosinase inhibitor. 2‐MNG binds to certain melanin precursors, preventing their integration into growing melanin and leading to inhibition of eumelanin and pheomelanin synthesis, without compromising the integrity of melanocytes.

Background: Within the solar ultraviolet (UV) spectrum, ultraviolet A rays (UVA, 320–400 nm), although less energetic than ultraviolet B rays (UVB, 280–320 nm), constitute at least 95% of solar UV radiation that penetrates deep into the skin The UV rays are associated with both epidermal and dermal damage resulting from the generation of reactive oxygen species (ROS). Among them, the longest UVA wavelengths (UVA1, 340–400 nm) can represent up to 75% of the total UV energy. Therefore, UVA radiation is linked to various acute and chronic conditions, including increased skin pigmentation and photoaging. Despite many advances in the skin photoprotection category, there is still a growing demand for natural daily photoprotection active ingredients that offer broad protection against skin damage caused by UVA exposure. In our quest to discover new, disruptive, next generation of photoprotective ingredients, we were drawn to pomegranate, based on its diverse polyphenolic profile. We investigated the pericarp of the fruit, so far considered as byproducts of the pomegranate supply chain, to design a novel patented extract “POMAOX” with a desired spectrum of phenolic components comprising of αβ-punicalagins, αβ-punicalins and ellagic acid. Methods: Antioxidant properties of POMAOX were measured using in-tubo standard tests capable of revealing a battery of radical oxygen species (ROS): peroxyl radical (ORAC), singlet oxygen (SOAC), superoxide anion (SORAC), peroxynitrite (NORAC), and hydroxyl radical (HORAC). In vitro, confirmation of antioxidant properties was first performed by evaluating protection against UVA-induced lipid peroxidation in human dermal fibroblasts (HDF), via the release of 8 iso-prostanes. The protection offered by POMAOX was further validated in a 3D in vitro reconstructed T-Skin^TM model, by analyzing tissue viability/morphology and measuring the release of Matrix Metallopeptidase 1 (MMP-1) & pro-inflammatory mediators (IL-1α, IL-1ra, IL-6, IL-8, GM-CSF, and TNF-α) after UVA1 exposure. Results: POMAOX displayed strong antioxidant activity against peroxynitrite (NORAC) at 1.0–3.0 ppm, comparable to the reference vitaminC, as well as singlet oxygen (SOAC) at 220 ppm, and superoxide radicals with a SORAC value of 500 ppm. Additionally, POMAOX demonstrated strong photoprotection benefit at 0.001% concentration, offering up to 74% protection against UVA-induced lipid peroxidation on HDF, in a similar range as the positive reference, Vitamin E at 0.002% (50 µM), and with higher efficacy than ellagic acid alone at 5 µM. Moreover, our pomegranate-derived extract delivered photoprotection at 0.001%, mitigating dermal damages induced by UVA1, through inhibition of MMP-1 and significant inhibition of pro-inflammatory mediators release (including IL-1α, IL-1ra, IL-6, IL-8, GM-CSF, and TNFα) on an in vitro reconstructed full-thickness human skin model with a similar level of protection to that of Vitamin C tested at 0.035% (200 µM). Conclusions: Overall, the novel pomegranate-derived extract “POMAOX” significantly reduced the impact of UVA on human skin, due to its broad-spectrum antioxidant profile. These findings suggest that POMAOX could offer enhanced protection against the detrimental effects of UV exposure, addressing the growing consumer demand for strong photoprotection with skincare benefits.

Hyperpigmentation disorders affect a large proportion of the population, significantly impacting their quality of life and carrying considerable social stigma. This growing global concern results in a strong demand for effective treatments. A rich body of literature proposes numerous active ingredients to solve hyperpigmentation concerns. At the same time, the complex regulation of skin pigmentation is much better understood with increased knowledge on the physiopathology of pigmentary disorders, beyond the sole melanogenesis, including the whole tissue environment of melanocytes. The abundance of mechanistic in vitro and in vivo scientific data makes it challenging for non-expert clinicians to identify the optimal care for patients. The aim of this review is to propose state-of-the-art of topical solutions with actives that have demonstrated conclusive clinical efficacy. It analyzes the different mechanisms involved, including the melanogenesis pathway and others addressing the melanocyte microenvironment. This review first examines the prevention of pigmentary disorders and the importance of a broad-spectrum photoprotection including the whole UV spectrum but also visible light in managing hyperpigmentation. The use of antioxidants to combat oxidative stress and complement photoprotection is also discussed. The following section reviews actives targeting the modulation of melanogenesis. It examines tyrosinase inhibitors, which are still widely used to manage hyperpigmentation problems, as well as new compounds targeting downstream pathways. Other clinically effective interventions include the normalization of epidermal homeostasis and the active restoration of the dermal fibroblastic microenvironment, together with anti-inflammatory agents and those aimed at reducing vascularization impact. Finally, this review highlights the value of combined approaches which have been shown to improve clinical efficacy. This suggests that future research should focus on well-tolerated, multifaceted therapies to effectively treat melanin hyperpigmentary disorders.