Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum–microbial metabolite–IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.

Background/Objective: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by diverse clinical manifestations. However, variations in its clinical presentations across different ages, genders, anatomical sites, and seasons remain incompletely understood. The objective was to explore the clinical heterogeneities of AD using data from the Chinese non-selective registration system. Methods: A prospective analysis was conducted on 3829 AD patients enrolled in the Chinese Non-selective Registry for AD (CNRAD) at hospital settings from 2020 to 2022. Demographic profiles; distribution, type, and severity of the skin lesion; laboratory findings; allergic comorbidities; family history; and exacerbating factors were analyzed. Results: The male-to-female ratio was 0.92 among adolescent and adult AD patients but increased to 2.11 in elderly AD patients, highlighting an age-dependent gender difference in AD prevalence. Age groups displayed distinct anatomical preferences for lesion distribution, with reduced involvement of the cubital and popliteal fossae in adult and elderly patients. Based on skin lesion characteristics, ten clinical subtypes of AD were proposed. Elderly AD patients exhibited higher severity, compared to adolescence and adult AD patients, with male patients being more severe than females. Elderly AD patients showed a lower proportion of extrinsic type, compared to childhood AD patients. Seasonal change emerged as the most important factor triggering AD flares. Conclusions: This study provides new insights into the heterogeneities of AD clinical manifestations in the Chinese population, demonstrating their significant dependence on temporal factors, including age and season.

The pilosebaceous units (PSUs) are essential micro‐organs for skin homeostasis, yet human vellus hair‐associated PSUs remain largely understudied. Here, we present a single‐nucleus transcriptomic atlas of PSUs from the back skin of healthy young and aged males, revealing extensive age‐associated cellular and transcriptional remodeling within this niche. We show that aging is accompanied by reduced relative representation of bulge hair follicle stem cells, together with altered regeneration‐associated transcriptional programs. Sebocytes display enhanced androgen responsiveness coupled with increased lipid biosynthetic activity during aging. Concurrently, an ion channel‐enriched follicular population shows increased representation with age and exhibits stress‐ and inflammation‐associated transcriptional features. In parallel, an innate immune‐like melanocyte subset shows reduced relative representation during aging, coinciding with changes in inferred melanocyte–immune communication. Notably, immune subsets in aged PSUs display coordinated changes in metabolic pathway signatures, suggesting an association between immune remodeling and metabolic state. Together, our findings highlight the aged PSU as a focal site where epithelial, immune, and metabolic alterations converge during skin aging. This work establishes a comprehensive single‐nucleus atlas of human vellus PSU aging and provides a framework for understanding how aging reshapes pilosebaceous niche biology, with potential implications for age‐associated cutaneous inflammation and dysfunction.