Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by impaired epidermal barrier function, persistent inflammation, and recurrent itching that substantially reduces patients' quality of life. Although dysregulated type 2 immune responses are recognized as major drivers of AD, emerging evidence indicates that lesional skin also exhibits abnormally high sodium chloride (NaCl) concentrations. While this high-salt microenvironment has been implicated in immune regulation, its direct effects on keratinocytes and skin barrier integrity have remained largely unexplored.

In a recent study published in Genes & Diseases, researchers from the Third Military Medical University (Army Medical University), Chongqing, investigated how a high-NaCl microenvironment modulates keratinocyte function and drives AD pathogenesis.

Using human keratinocyte (HaCaT) models, the investigators observed that elevated extracellular NaCl concentrations induce a concentration-dependent downregulation of the key epidermal barrier proteins filaggrin (FLG) and loricrin (LOR). Concurrently, high-salt exposure increased the transcription and secretion of pro-inflammatory cytokines, specifically interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP).

Mechanistically, the study demonstrated that NaCl activates the serum and glucocorticoid-regulated kinase 1 (SGK-1) pathway in keratinocytes. High-salt stimulation triggers SGK-1 phosphorylation, prompting its physical association with tuberous sclerosis complex 2 (TSC2), which was validated via co-immunoprecipitation assays. Activated SGK-1 phosphorylates TSC2, which subsequently activates the mechanistic target of rapamycin (mTOR) pathway. This downstream activation drives the phosphorylation of STAT3 and the nuclear translocation of the NF-κB subunits p65 and p50. Pharmacological inhibition of mTOR using rapamycin or siRNA-mediated knockdown of SGK-1 suppressed this signaling cascade, confirming that the mTOR pathway acts downstream of SGK-1/TSC2 to repress FLG and LOR transcription while promoting cytokine expression.

The physiological relevance of this pathway was validated in vivo using a dinitrofluorobenzene (DNFB)- and ovalbumin (OVA)- induced murine model of dermatitis. Under high-salt conditions, mice displayed aggravated skin lesions, elevated trans-epidermal water loss (TEWL), and increased cytokine production. However, genetic knockdown of SGK-1 or pharmacological treatment with the SGK-1 inhibitor GSK 650394 reversed these effects. Furthermore, combining the SGK-1 inhibitor with the JAK inhibitor delgocitinib improved barrier recovery, showing reduced dermatitis scores, decreased TEWL, and restored FLG and LOR expression compared to monotherapies.

In conclusion, this study identifies the SGK-1/TSC2/mTOR axis as a regulator of NaCl-induced barrier dysfunction and inflammation in AD. These findings indicate that targeting SGK-1 signaling, particularly in combination with JAK inhibition, may provide a therapeutic strategy for managing salt-exacerbated inflammatory skin conditions. The authors suggest that further clinical studies are warranted to evaluate these combination regimens in patient populations.

Reference

Title of Original Paper: High-salt microenvironment worsens the progression of atopic dermatitis via activating the SGK–1–mTOR pathway in keratinocytes

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2026.102168

Funding Information:
The National Natural Science Foundation of China (No. 82304032)
The Natural Science Foundation of Chongqing, China (No. CSTB2023NSCQ-MSX1081)
The Science and Technology Research Program of Chongqing Education Commission of China (No. KJQN202312808, KJZD-k202312804)

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