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Epidermal retinoid starvation driven by AKR1B10 orchestrates barrier disruption and hyperinflammation in atopic
Fugang Xiao1, Kerui Chen1, Jialan Li1
1Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan Province, People's Republic of China.
Background:
Atopic dermatitis (AD) is driven by a feed-forward loop of epidermal barrier disruption and immune dysregulation. Although retinoic acid (RA) signaling is indispensable for epidermal homeostasis and terminal differentiation, the molecular mechanisms underlying its functional exhaustion in eczematous lesions remain incompletely elucidated. To investigate whether the aldo-keto reductase AKR1B10 mediates intracellular RA depletion and epidermal dysfunction in AD, and to evaluate the therapeutic potential of topical aldo-keto reductase inhibition.
Methods:
We integrated single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and spatial transcriptomic datasets to identify AKR1B10 as a severity-associated metabolic candidate. In vitro, we performed siRNA-mediated knockdown and plasmid-based overexpression of AKR1B10 in HaCaT and primary human keratinocytes (NHEKs), complemented by RAR antagonist (AGN193109) blockade and exogenous atRA rescue. In vivo, we tested topical fidarestat in an MC903/OVA-induced AD mouse model.
Results:
AKR1B10 was significantly upregulated in AD keratinocytes, preferentially enriched in the stratum spinosum, and positively correlated with patient SCORAD scores (r = 0.70). AKR1B10 overexpression depleted intracellular atRA (validated by targeted LC-MS/MS), downregulated barrier proteins (FLG, KRT10, CLDN1), and induced pro-inflammatory mediators (IL-6, IL-8, CXCL1). AGN blockade abrogated the protective effects of AKR1B10 knockdown, while exogenous atRA rescued the overexpression phenotype. Topical fidarestat restored cutaneous atRA availability and RA target gene expression (CYP26A1, CRABP2), repaired epidermal architecture, and attenuated AD-like inflammation in vivo.
Conclusion:
AKR1B10 acts as a localized enzymatic sink that depletes intracellular RA pools, linking metabolic dysregulation to barrier disruption and hyperinflammation in AD. Topical aldo-keto reductase inhibition represents a promising, mechanistically grounded barrier-restorative strategy, although definitive AKR1B10-specific in vivo validation requires further study.