Entagenic acid targets ASCC2 to ameliorate allergic contact dermatitis via repressing NF‑κB transactivation and chemokine expression

  • Phytomedicine. 2026 Aug:158:158374. doi: 10.1016/j.phymed.2026.158374.
Hui Xiong  1 ,  Jiayue Yu  1 ,  Ningbo Zhang  2 ,  Ruilin Li  3 ,  Ting Yan  1 ,  Xiaocong Wang  4 ,  Jingbo Zheng  4 ,  Wen Zhang  4 ,  Juan Yang  5 ,  Zhinan Mei  6
Affiliations
  • 1. School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
  • 2. College of Plant Science & Technology, Huazhong Agricultural University, Wuhan 430070, China.
  • 3. Gannan Institute of Innovation and Translational Medicine, State Key Laboratory of New Targets and Drug Development for Major Diseases, Gannan Medical University, Ganzhou 341000, China.
  • 4. College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
  • 5. Gannan Institute of Innovation and Translational Medicine, State Key Laboratory of New Targets and Drug Development for Major Diseases, Gannan Medical University, Ganzhou 341000, China. Electronic address: [email protected].
  • 6. School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China; College of Plant Science & Technology, Huazhong Agricultural University, Wuhan 430070, China. Electronic address: [email protected].
PMID: 42269183 DOI: 10.1016/j.phymed.2026.158374
Abstract

Background: Allergic Contact Dermatitis (ACD) is an inflammatory Skin Disease triggered by allergen exposure. Entagenic acid (EA) is the main triterpene aglycone isolated from Entada phaseoloides, which has been documented to treat dermatitis, exhibits anti-inflammatory properties. However, its molecular mechanism in ACD remains unexplored.

Purpose: This study aimed to investigate the therapeutic effect of EA against ACD and explore its underlying molecular target and mechanism.

Methods: The therapeutic effect of EA on ACD was evaluated in TNF-α/IFN-γ-stimulated keratinocytes and Squaric acid dibutylester (SADBE)-induced ACD mouse models. Integrated approaches including DrugBAN, GraphDTA, and thermal proteome profiling identified Activating Signal Cointegrator 1 Complex Subunit 2 (ASCC2) as the direct target of EA, which was confirmed by CETSA and ITC. The mechanism of EA targeting ASCC2 to alleviate keratinocytes inflammation was elucidated through transcriptomics, co-immunoprecipitation, and RNA interference. In vivo, intradermal injection of rAAV.DJ-CMV-ASCC2 was used to verify the ASCC2-dependent therapeutic effect of EA in ACD mice.

Results: Our study revealed that EA suppressed the expression of CXCL10 and CCL2 in keratinocytes and alleviated ACD-like symptoms in mice. EA decreased the mRNA levels of chemokines and regulated the NF-κB pathway through interrupting the interaction between ASCC2 and p65 in keratinocytes. In vivo, we also demonstrated that the overexpression of ASCC2 on skin of ACD mice reduced the EA-induced therapeutic effect.

Conclusion: Our findings demonstrate that EA directly binds to ASCC2, attenuates NF-κB pathway transactivation, reduces key chemokine expression, and suppresses ACD-like progression, highlighting its potential as a therapeutic candidate for ACD.

Keywords
ASCC2; Allergic contact dermatitis; CCL2; CXCL10; Entagenic acid; Keratinocytes.
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