Atopic dermatitis (AD) is a widespread chronic skin disorder characterized by recurring, pruritus and inflammatory symptoms (Langan et al., 2020). AD has a multifactorial pathogenesis, primarily including compromised skin barrier function, heightened immune reactivity, and the interplay between genetic predisposition and environmental influences (Langan et al., 2020; Leung and Guttman-Yassky, 2014). Recent studies increasingly suggest that the integrity and function of the epidermal barrier are crucial factors in AD development (Egawa and Kabashima, 2016). Null mutations targeting the filaggrin gene, which is responsible for a key epidermal barrier protein, impair the skin's barrier function and contribute to the development of spontaneous AD-like dermatitis (Kawasaki et al., 2012; Palmer et al., 2006). Impairment of the epidermal barrier function exacerbates the engagement between environmental antigens and immune cells within the skin, initiating a localized inflammatory response (Elias and Steinhoff, 2008). Therefore, targeting the maintenance and restoration of skin barrier function is a key strategy for effectively treating AD and preventing the onset of related allergic diseases. Current therapeutic strategies for AD predominantly rely on antihistamines, corticosteroids and immunosuppressants. While these agents demonstrate significant efficacy in alleviating the clinical symptoms of AD, their long-term administration is frequently associated with adverse effects, such as compromised skin integrity (fragility) and increased susceptibility to infections (Patel and Khan, 2017). Consequently, there remains a pressing need to develop novel anti-AD pharmaceuticals with more favourable long-term tolerability.

Autophagy is a fundamental, evolutionarily conserved process by which cells eliminate and recycle their own damaged or unnecessary components to maintain homeostasis (Klionsky et al., 2021). The autophagic process involves the formation of double-membrane autophagosomes that encapsulate misfolded proteins and dysfunctional organelles, followed by fusion with lysosomes to degrade the cargo (Feng et al., 2014). Recent studies indicate that dysfunctional autophagy contributes to the pathogenesis of various skin autoimmune disorders, including AD (Lin et al., 2024). Consistent with this, RNA sequencing analyses have suggested that abnormal expression of key autophagy-related proteins (ATGs), such as ATG16L2, ATG4s, and ULK1, is associated with AD development (Blunder et al., 2018). The epithelium of both AD patients and mouse models of AD exhibits decreased levels of the autophagosome marker microtubule-associated protein light chain 3 (LC3) and concurrently increased levels of the selective autophagy substrate sequestosome-1/p62(Peng et al., 2022). Moreover, a significant reduction in the activity of functional lysosomal proteases, such as cathepsins D and L, within AD skin lesions (Klapan et al., 2021) provides additional evidence suggesting that the autophagy-lysosome pathway is impaired in this condition. Beneficial effects of autophagy induction in AD models have been reported. Rapamycin, an autophagy inducer, has been shown to alleviate AD-like symptoms in NC/Nga mice (Jung et al., 2015). Additionally, human β-defensin-3 was shown to improve the epithelial barrier and reduce inflammation associated with AD by activating keratinocyte autophagy (Peng et al., 2022). Collectively, these findings indicate that promoting autophagy could represent a valuable therapeutic strategy for AD.

Escin (also termed aescin or β-escin), a natural saponin extracted from Aesculus hippocastanum (horse chestnut) seeds, possesses well-documented anti-inflammatory, antioxidant, and anti-edematous properties demonstrated in various clinical models (Gallelli, 2019). Escin has been reported to activate autophagy and facilitate the degradation of mutant huntingtin proteins in neuronal HT22 cells (Sun et al., 2020). Furthermore, a recent study demonstrated that escin induces autophagy through the Nrf2 (nuclear factor E2-related factor 2) pathway, consequently alleviating lipid accumulation and oxidative stress in liver cells (Yu et al., 2023). While escin has been demonstrated to modulate autophagy in various cell types, its specific influence on autophagic processes within skin cells, and consequently its therapeutic potential for AD, remain largely undetermined.

This study is designed to investigate the regulatory effects of escin on autophagy within skin cells and to elucidate the underlying molecular mechanisms. Utilizing both in vitro and in vivo experimental models, we aim to determine whether escin could ameliorate AD symptoms through the activation of the autophagy-lysosome pathway, thereby providing novel insights and potential therapeutic strategies for the management of AD.