Th2 cell-mediated ferroptosis as a driver of sebaceous gland dysfunction in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by reduced sebum production and skin dryness, yet the functional states of the sebaceous gland (SG, a key tissue for sebum production) in the pathogenesis of AD remain unclear. We fully explored the number, morphology, and function of SG in AD through multiomics, animal intervention experiments, and mechanistic studies. Integrated high-resolution and spot-level spatial transcriptomics, single-cell/bulk RNA sequencing, metabolomics, and histological analysis revealed a marked reduction in SG number in AD, accompanied by morphological atrophy and impaired lipid metabolism, which was closely associated with elevated ferroptosis levels in SG. Topical application of the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly ameliorated AD-like dermatitis in MC903-treated mice, restoring SG morphology and function, while reducing Th2 cell infiltration and lowering transepidermal water loss (TEWL). Spatial transcriptomic mapping and immunofluorescence localization demonstrated Th2 cells exhibited the strongest spatial proximity to SG in AD lesional skin, indicating the effect of Th2 cells on ferroptosis in SG. Further communication profiling indicated that Th2-derived IL-4 may target GPX4 in SG. In vitro, treatment of SG cells (SZ95) with IL-4 increased ferroptosis levels and decreased GPX4 protein expression. Mechanistically, IL-4 enhanced the binding between TRIM15 and GPX4, which mediated the K48-linked ubiquitination and degradation of GPX4. Consistently, blockade of IL-4 or IL-4Rα using an anti-IL-4 antibody or dupilumab effectively alleviated SG ferroptosis, reduced TEWL, and attenuated the severity of AD-like dermatitis. Our study reveals a mechanistic link between Th2 inflammation and SG ferroptosis via IL-4-TRIM15-GPX4-ubiquitination signaling, thus offering new insights into SG dysfunction and skin barrier impairment in AD. CLINICAL IMPLICATIONS: Reduced sebum production and skin dryness are  notable clinical  manifestations of atopic dermatitis (AD). Our study revealed that ferroptosis of the sebaceous gland (SG) may disrupt sebum production in AD, thus offering new insight into AD therapy by highlighting sebum homeostasis as a potential therapeutic target. Sebaceous gland (SG) ferroptosis,  which contributes to reduced sebum production and skin barrier dysfunction in atopic dermatitis (AD), is driven by Th2 cell-derived IL-4  via TRIM15/GPX4 ubiquitination.