雅诗兰黛集团

BACKGROUND:Botanicals are widely used in topical formulations for cosmetics, hair care, and personal care products, reflecting consumer interest in plant-derived materials. Their complex and variable composition, presents challenges for traditional toxicological approaches developed for single chemicals. Although many botanicals are well tolerated, reports of skin irritation, sensitization, and phototoxicity highlight the need for reliable approaches to identify dermal hazards and evaluate risk. Established in silico, in chemico, and in vitro test methods, often referred to as New Approach Methodologies (NAMs), may offer efficient and mechanistically informed tools. OBJECTIVE:The Dermal Working Group within the Botanical Safety Consortium (BSC) developed a strategy for evaluating existing NAMs for assessing dermal toxicity endpoints in botanicals, using literature evidence and data-rich botanicals to inform assay selection and anticipated performance. This narrative review describes the literature-based considerations used to select candidate assays and characterized reference botanicals for subsequent experimental evaluation. METHODS:This narrative review describes considerations in the selection and application of in vitro and in chemico assays addressing skin irritation (OECD TG 439), phototoxicity (OECD TG 432), and skin sensitization (OECD TG 442 C, 442D, and 442E), together with in silico approaches. RESULTS & DISCUSSION:A set of reference botanicals spanning a range of expected outcomes, from botanicals not expected to have effects to known irritants, sensitizers, and phototoxicants, was chosen to provide a foundation for evaluating assay performance and identifying technical considerations. CONCLUSION:This manuscript describes the botanicals and assays being evaluated as part of the BSC's planned dermal toxicity work. The goal of this work is to investigate the utility of NAMs for dermal safety evaluations of botanicals.

Ferroptosis, an iron-dependent form of regulated cell death, is crucial for skin homeostasis and pathology. The H3K36-specific dimethyltransferase NSD2 is a key epigenetic regulator involved in a spectrum of physiological processes and contributes to the pathogenesis of various human cancers. However, the epigenetic mechanism governing ferroptosis sensitivity in keratinocytes remains poorly understood. This study revealed the role of NSD2 in regulating ferroptosis in HaCaT keratinocytes. We demonstrated that NSD2 deletion significantly attenuated Erastin-induced redox imbalance and reduced the sensitivity of HaCaT cells to Erastin-induced ferroptosis. RNA-seq analysis revealed that NSD2 deficiency downregulated key ferroptosis-promoting genes, including NCOA4, LPCAT3, and ATG5. Mechanistically, NSD2-mediated H3K36me2 activates their transcription to facilitate ferroptosis in keratinocytes. In addition, functional rescue experiments showed that restoring NCOA4, LPCAT3 or ATG5 expression reversed the ferroptosis resistance caused by NSD2 deficiency. This study identifies NSD2 as a novel critical epigenetic regulator of ferroptosis. It unveils that NSD2 is essential for ferroptosis by synchronously enhancing iron accumulation and lipid peroxidation substrate supply. This provides a new mechanistic link between epigenetic regulation and ferroptosis-related cell fate determination in the skin.

Glycation and reactive carbonyl stress are protein-modifying processes associated with skin aging, but how they alter local tissue mechanics and deformation-prone behavior remains unclear. Here, reconstructed human epidermis (RHE) and three-dimensional (3D) collagen gels were used as epidermal-like and collagen-rich skin surrogate compartments. Nanoindentation mapping showed that accelerated glycation and carbonyl stress increased the effective Young’s modulus and stiffness heterogeneity in both models, with 2.34–5.85-fold increases in the mean modulus and 1.09–1.31-fold increases in normalized neighbor contrast across four treatment–model combinations: glycated RHE, glycated 3D collagen gel, carbonyl-stressed RHE and carbonyl-stressed 3D collagen gel. Nanoindentation-derived stiffness profiles were incorporated into reduced-order virtual bilayer nonlinear post-buckling simulations. Under imposed end-shortening strains of 1%, 5%, and 10%, glycation- and carbonyl-stress-informed bilayers showed increased predicted peak curvature and localized folding index values. Profile-control simulations were then used to separate average stiffening from spatial stiffness variation. Uniform-mean profiles failed to reproduce the curvature localization response, whereas heterogeneity-preserving mean-matched profiles retained elevated curvature-based outputs. These findings suggest that spatial stiffness heterogeneity, rather than stiffening alone, contributes to predicted curvature localization in skin surrogate bilayers. Beyond mechanistic insight, the nanoindentation–simulation workflow may provide a mechanics-based readout for evaluating prospective cosmetic interventions.

The acidic microenvironment of the stratum corneum is crucial for epidermal desquamation and barrier homeostasis, yet the primary proton sensor that triggers this process remains unknown. Here, we report that the proton-activated chloride channel PACC1 is essential for acid-induced upregulation of kallikreins (KLKs) and desmosomal degradation, two key steps in skin exfoliation. Functional and protein expression analyses revealed that PACC1 is the predominant acid-sensitive ion channel in keratinocytes. Proton-mediated PACC1 activation evokes chloride efflux and initiates a signaling cascade via the c-Jun N-terminal Kinase/AP-1 (JNK/AP-1) pathway. This cascade significantly enhances the expression and secretion of KLKs (KLK5/7), thereby facilitating desquamation through corneodesmosomal degradation. Notably, acid-induced KLK upregulation was abolished by PACC1 knockdown, knockout, or mutants that are deficient in proton sensing. This effect was also observed with pharmacological channel inhibition and was specifically restored by reconstitution with functional PACC1. These findings establish PACC1 as the core sensor that converts epidermal acidification into a desquamation signal, providing a mechanistic foundation for developing targeted therapeutic and cosmetic strategies that modulate skin barrier function.