Chebulinic acid suppresses NF-κB/TSLP signaling axis via ACLY-mediated lipid metabolism reprogramming to ameliorate atopic dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia chebula Retz. (Combretaceae) is a classic medicinal plant in Tibetan medicine, Ayurveda, and Traditional Chinese Medicine. It is traditionally applied to relieve pruritus, erythema and xerosis, which are typical clinical manifestations of atopic dermatitis (AD), and these traditional applications have been scientifically verified. Chebulinic acid (CA), a major phenolic constituent of this plant, inherits its traditional anti-inflammatory and skin-protective potentials.

AIMS OF THIS STUDY: This study aimed to explore the therapeutic potential of CA against AD and clarify its underlying mechanism targeting the lipid metabolism-NF-κB/TSLP axis.

METHODS

FLG-knockout (Flg-/-) mice were divided into six groups to assess skin lesion severity through various measures including ear thickness and histopathology. In vitro, transcriptome and mechanistic analyses were performed in IL-4/IL-13-stimulated HaCaT cells to identify key signaling pathways.

RESULTS

Topical CA application significantly ameliorated AD-like symptoms in Flg-/- mice, reducing epidermal thickening, improving lesion scores, enhancing skin barrier function (decreased TEWL), and inhibiting keratinocyte proliferation. CA also reduced serum IgE and TSLP levels, diminished CD4+ T cell infiltration, and downregulated Th2 cytokines (IL-4, IL-5, IL-13) in lesional skin. In vitro, CA suppressed pro-inflammatory mediators (IL-6, IL-8, TSLP) in AD-like keratinocytes. Transcriptomic and pathway analyses revealed that CA targets the ACLY/NF-κB/TSLP axis: CA inhibited ACLY, reducing acetyl-CoA availability, which in turn suppressed NF-κB p65 (RELA) acetylation at K310-critical for TSLP transactivation. This mechanism was validated using the ACLY-specific inhibitor BMS-303141, and further corroborated by genetic ACLY knockdown and acetyl-CoA rescue experiments, which collectively recapitulated CA's inhibitory effects on p65 acetylation and TSLP expression.

CONCLUSIONS

Our findings demonstrate that CA ameliorates AD by disrupting the ACLY-mediated metabolic-immune loop, linking fatty acid metabolism to NF-κB/TSLP-driven inflammation. This identifies CA as a promising multifaceted therapeutic agent for AD, targeting both barrier dysfunction and immune dysregulation via a novel regulatory axis.