The formula, known as gu-ben-hua-shi, or AESS, was developed by Professor Dacan Chen and descends from the san-shu formula first recorded in a Qing dynasty materia medica from 1767. It combines Atractylodes rhizomes, zedoary, honeysuckle flower, sophora flower, coix seed, fangfeng root and rehmannia root in proportions designed, in traditional terms, to invigorate the spleen and eliminate dampness. In modern terms, the study published in the Journal of Cellular and Molecular Medicine set out to determine whether this centuries-old prescription works through the Hippo-YAP signalling pathway, a master regulator of keratinocyte growth and differentiation, and through autophagy, the cellular recycling process that keeps the epidermis functional.

The evidence came from three complementary lines of investigation. First, a prospective single-arm clinical trial enrolled 34 adults with moderate-to-severe atopic dermatitis, 97 percent of whom fell into the moderate or severe category. Participants drank the AESS decoction twice daily for eight weeks while using standardized moisturizers, with no steroids or other topical anti-inflammatory drugs permitted. Second, the team ran network pharmacology and animal studies in dust-mite-induced atopic dermatitis mice. Third, they tested AESS-containing serum on human keratinocytes grown under inflammatory conditions mimicking the disease.

The clinical results were striking. After eight weeks, the mean SCORAD score fell from 44.8 to 11.6, the EASI score dropped from 9.2 to 1.1, and the Investigator’s Global Assessment fell from 2.9 to 0.6, all highly significant changes. Nearly a quarter of patients achieved a 90 percent improvement in SCORAD, and almost three-quarters achieved at least a 50 percent improvement. Itching and sleep scores improved substantially, as did quality-of-life measures. On instrumental testing, transepidermal water loss, a gold-standard marker of barrier leakiness, fell significantly in lesional skin, while stratum corneum hydration rose significantly in non-lesional skin. Blood tests showed eosinophil counts dropping sharply and the Th1/Th2 and Treg/Th17 immune ratios shifting toward balance. Only two adverse events were recorded, both common colds judged unrelated to treatment.

To understand how a mixture of plant extracts could produce such effects, the researchers first used ultra-high-performance liquid chromatography coupled with tandem mass spectrometry to catalogue the chemistry. They detected 91 compounds and identified 76, including organic acids, terpenoids, flavonoids and diarylheptanoids. Ten of the most abundant compounds surviving into the bloodstream, among them chlorogenic acid, rutin and narcissoside, were then fed into network pharmacology databases to map their likely protein targets against known atopic dermatitis genes. The analysis converged on 326 overlapping targets and highlighted 30 core candidates, including TNF, TP53, SRC, IL-6 and mTOR, with enriched pathways pointing squarely at autophagy, mTOR signalling and immune regulation.

The animal experiments then delivered the causal evidence. In mice whose dermatitis was induced by repeated application of house dust mite extract, oral AESS reduced dermatitis scores, ear thickness and lesion thickness, lowered transepidermal water loss and raised skin hydration in a dose-dependent manner. Crucially, when the researchers silenced YAP, the key downstream effector of the Hippo pathway, using lentiviral shRNA injected into the lesions, the benefits of AESS largely evaporated: dermatitis scores climbed back, barrier proteins fell and inflammation returned. Dexamethasone, the positive control, suppressed inflammation but actually damaged the barrier, increasing water loss and reducing hydration while cutting levels of the barrier proteins filaggrin, involucrin and loricrin.

The mechanistic story centres on the Hippo kinase cascade. In atopic dermatitis, whether in mouse skin or in human keratinocytes stimulated with interferon-gamma and tumour necrosis factor-alpha, YAP expression drops while its inhibitory phosphorylation rises, driven by activated MST1/2 and LATS1/2 kinases that trap YAP in the cytoplasm. AESS treatment reversed this pattern, reducing phosphorylation of the cascade and allowing YAP to accumulate in the nucleus, where it can switch on genes for keratinocyte proliferation and differentiation. Barrier proteins filaggrin, involucrin and loricrin, which build the structural scaffolding of the stratum corneum, rose in step with YAP restoration and fell again when YAP was knocked down, in both mice and cell cultures.

Autophagy emerged as the second arm of the mechanism. Reduced autophagy is increasingly recognized as a feature of atopic dermatitis, impairing keratinocyte differentiation and defence against pathogens such as Staphylococcus aureus. In the diseased mice and cells, the researchers observed fewer autophagosomes and autolysosomes under the electron microscope, reduced LC3 lipidation and elevated p62, together with heightened mTOR activity, mTOR being a known brake on autophagy. AESS restored autophagic flux in a dose-dependent manner, boosting LC3, lowering p62 and dampening p-mTOR, and tandem mRFP-GFP-LC3 assays confirmed that the flux through autolysosomes genuinely accelerated rather than merely stalled. Immunofluorescence showed YAP and LC3 co-localizing after treatment, and YAP knockdown abolished the autophagy boost, placing YAP upstream of the autophagy programme.

The cell experiments rounded out the picture. AESS-containing serum, tested at 5, 10 and 15 percent concentrations, increased the proliferation of inflamed keratinocytes and reduced their apoptosis, effects again reversed by YAP silencing. The authors suggest this dual action, simultaneously rebuilding the physical barrier through YAP-driven differentiation and autophagy while calming the Th2- and Th17-skewed immune storm, addresses the two principal drivers of atopic dermatitis in one intervention, something no single conventional drug currently achieves without barrier side effects.

The researchers are careful about the limits of the work. The clinical arm was a small, uncontrolled, single-arm pilot without a placebo group, so expectation effects cannot be excluded, and the eight-week follow-up cannot speak to long-term safety or relapse. A placebo-controlled randomized trial is now under way. The network pharmacology, while suggestive, relies on prediction databases, and the precise compound or compounds within the 76 identified constituents that activate the Hippo-YAP axis remain unidentified. Still, the convergence of clinical improvement, dose-dependent animal efficacy, genetic loss-of-function confirmation and cellular mechanism is unusual rigor for a traditional medicine study, and it offers a template for how classical formulas might be validated and mechanistically dissected. If the ongoing randomized trial confirms these findings, an eight-herb decoction first described in 1767 could earn a place in the modern eczema arsenal, not as folklore but as a multi-target therapy that teaches damaged skin to repair itself.

Subject of Research: Mechanism of a traditional Chinese herbal formula regulating autophagy via the Hippo-YAP pathway to restore the skin barrier in atopic dermatitis

Article Title: Mechanism of Gu‐Ben‐Hua‐Shi (AESS) Formula Regulating Autophagy Through Hippo‐YAP Pathway in Restoring the Skin Barrier in Atopic Dermatitis

Article References: Ma, X., Huang, Y., Lv, X., Mo, X., Liu, J., Yan, F., Ye, S., Zhang, Y., Chen, D., & Jia, J. (2026). Mechanism of Gu‐Ben‐Hua‐Shi ( AESS ) Formula Regulating Autophagy Through Hippo‐ YAP Pathway in Restoring the Skin Barrier in Atopic Dermatitis. Journal of Cellular and Molecular Medicine, 30(17), Article e71361. https://doi.org/10.1111/jcmm.71361

Image Credits: AI Generated

DOI: 10.1111/jcmm.71361

Keywords: atopic dermatitis, traditional Chinese medicine, Hippo-YAP pathway, autophagy, skin barrier, filaggrin, transepidermal water loss, keratinocytes, mTOR, clinical trial, network pharmacology, eczema