Foxn1 regulates epidermal structure, redox balance, and age related changes

Abstract

Skin aging is a complex process, marked by structural decline, functional impairment, and diminished regenerative capacity. In this study, we shine a spotlight on the transcription factor Foxn1 and its pivotal role in modulating age-related changes in skin architecture and redox homeostasis. Using a murine model across three life stages (young — 20-days-old, middle-age — 1-year-old, old — 2-year-old), we compared wild-type (Foxn1 +/+ ) and Foxn1 heterozygotic knock out (Foxn1 + / -  ) mice to unravel the interplay between genetic regulation and skin aging. Our findings reveal a striking impact of Foxn1 on skin morphology: Foxn1 +/- mice displayed thinner epidermis, thicker dermis, and disrupted keratinocyte differentiation, favoring large spinous layer of epidermal cells. Notably, the skin of Foxn1 +/+ mice was associated with increased collagen I and a shift toward repair-oriented fibers, whereas Foxn1 +/- skin maintained elevated collagen III, hinting at a preserved regenerative profile. Additionally, while p21 expression rose with age in Foxn1 +/+ mice, it remained low in Foxn1 +/- mice, suggesting an altered senescence pathway. Intriguingly, Foxn1 also emerged as a modulator of the hypoxia response, oxidative stress levels, and cellular protection, particularly in young and middle-age mice. These effects diminished with advanced age, underscoring Foxn1’s age-dependent regulatory dynamics. Together, these results position Foxn1 as one of key regulators of skin homeostasis and reveal its potential role in skin aging processes.