Abstract

Background

   Atopic dermatitis (AD) is a common pediatric skin disease, with recent
   studies suggesting a role for ferroptosis in its pathogenesis. Sodium
   propionate (SP) has shown therapeutic potential in AD, yet its
   mechanism, particularly regarding ferroptosis modulation, remains
   unclear. This study aims to explore whether SP alleviates AD by
   modulating ferroptosis-related pathways through bioinformatic and in
   vitro analyses.

Methods

   We analyzed the GEO AD cohort ([38]GSE107361). Ferroptosis-related
   genes was compiled from the GeneCards Database and SP-associated
   therapeutic target genes were obtained from Swiss Target Prediction. To
   explore potential biological mechanisms, we employed Gene Set Variation
   Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes
   and Genomes (KEGG) analyses. Weighted Gene Co-expression Network
   Analysis (WGCNA) and differential expression analysis identified key
   gene modules. We also established TNF-α/IFN-γ induced AD cell models
   using HaCat cells and collected cell samples for further experiments.

Results

   The GSVA analysis demonstrated that ferroptosis-related genes could
   differentiate between healthy children and those with AD. The
   identified module includes genes with correlated expression patterns
   specifically linked to AD. Analysis using three algorithms identified
   potential therapeutic targets of SP. We screened 51 key genes related
   to AD and ferroptosis, selecting cyclin-dependent kinase 1 (CDK1) and
   latent transforming growth factor beta binding protein 2 (LTBP2) as
   co-expressed genes. Machine learning identified fatty acid binding
   protein 4 (FABP4) as a significant gene intersection of the 51 key
   genes. The bioinformatics analysis results were validated through cell
   experiments, showing that SP treatment increased the expression of the
   damaged skin genes loricrin (LOR) and filaggrin (FLG).

Conclusion

   Our study indicates that SP may alleviate AD symptoms by modulating
   ferroptosis through the LTBP2/FABP4 pathway.

   Keywords: atopic dermatitis, ferroptosis, bioinformatics, propionate

Introduction

   Atopic dermatitis (AD) is a chronic inflammatory skin disease with
   significant variations in prevalence among children, ranging from 2.7%
   to 20.1% among 65,661 participants.[39]^1 This skin disorder causes
   itching, one of its most unbearable symptoms. The pathophysiology of AD
   involves various immune cells and chemokines, including interleukin-4
   (IL-4) and interleukin-13 (IL-13).[40]^2 In chronic phase, Th1
   polarization and the Th17 pathway are impaired.[41]^3 Cell death has
   long been a focal point of research on various diseases. Recent studies
   have demonstrated that AD is closely associated with
   pyroptosis[42]^4^,[43]^5 and apoptosis.[44]^6^,[45]^7 These cell death
   patterns are significantly linked to oxidative stress.[46]^8^,[47]^9
   Many studies are exploring emerging treatments that show great promise
   for AD. Ferroptosis, a novel mode of cell death, has been identified in
   immune diseases.[48]^10^,[49]^11 Recent studies indicate that immune
   cells can undergo ferroptosis.[50]^10 Ferroptosis plays a crucial role
   in regulating oxidative stress and the inflammatory response.[51]^12
   Inhibiting ferroptosis can significantly alleviate oxidative stress and
   reduce disease states, such as cognitive impairment in rats with
   chronic cerebral hypoperfusion,[52]^13 corneal damage in
   xerophthalmia[53]^14 and emphysema.[54]^15 Blocking ferroptosis can
   diminish the inflammatory response.[55]^16^,[56]^17 Studies have shown
   that inhibiting ferroptosis alleviates psoriasis-related
   inflammation,[57]^18 reduces skin inflammation caused by UV-B
   radiation[58]^19 and diminishes cartilage inflammation in
   arthritis.[59]^20 Researches show that hydrogels can reduce
   scratch-induced intercellular inflammation by scavenging intracellular
   reactive oxygen species (ROS). They alleviate skin inflammation and
   help reconstruct the skin barrier in AD mice.[60]^21–23 Oxidative
   stress is associated with inflammation.[61]^24^,[62]^25 Significant
   oxidative stress has also been detected in ferroptosis.[63]^10^,[64]^25
   Analyses of public databases have demonstrated that ferroptosis-related
   genes play significant roles in AD.[65]^26 Ptgs2 is a crucial gene
   involved in ferroptosis.[66]^27 A recent bioinformatics analysis
   examined four datasets and identified four ferroptosis-related genes
   (ALOXE3, FABP4, MAP3K14, and EGR1) as potential therapeutic biomarkers
   for AD.[67]^26 This study aimed to identify and validate the
   therapeutic targets of ferroptosis in AD.

   Current treatment options for AD are categorized as local and systemic
   therapies, including corticosteroids, calcineurin inhibitors, and Janus
   kinases (JAK) inhibitors.[68]^28 Researchers have primarily focused on
   baricitinib and upadacitinib among the JAK inhibitors. Studies indicate
   that baricitinib effectively treats moderate to severe AD by
   significantly improving symptoms and reducing pruritus.[69]^29
   Upadacitinib also demonstrates good efficacy and safety; however,
   predict its effectiveness need to be further investigated.[70]^30–32
   These JAK inhibitors possess distinct advantages in the treatment of
   AD, providing more treatment options and references for clinicians and