PJ‑001, a small‑molecule proteolysis‑targeting chimera, ameliorates atopic dermatitis‑like inflammation in mice by inhibiting the JAK2/STAT3 pathway and repairing the skin barrier

Lin,Pei; Chen,Zhendong; Lu,Yinying; Shi,Hongyu; Lin,Jun

doi:10.3892/etm.2024.12464

PJ‑001, a small‑molecule proteolysis‑targeting chimera, ameliorates atopic dermatitis‑like inflammation in mice by inhibiting the JAK2/STAT3 pathway and repairing the skin barrier

Authors:
- Pei Lin
- Zhendong Chen
- Yinying Lu
- Hongyu Shi
- Jun Lin
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Affiliations: School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
Published online on: February 29, 2024 https://doi.org/10.3892/etm.2024.12464
Article Number: 176

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Abstract

Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ‑001 is a small‑molecule proteolysis‑targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4‑dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ‑001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll‑like receptor 4/nuclear factor‑κB (TLR4/NF‑κB), Beclin 1 and microtubule‑associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription‑PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin‑10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ‑001, the AD‑like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF‑κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ‑001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ‑001 could be considered a potential therapeutic option for AD.

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