Authors
Xinyue Zhang, Ruiqi Li, Lijun Sun, Yi Zheng, Tong Zhou, Yifan Xia, Mengyao Yi, Delu Che, Songmei Geng
Published in
The Journal of investigative dermatology. Oct 28, 2026. Epub Oct 28, 2026.
Abstract
Epigenetic dysregulation is implicated in inflammatory skin diseases such as rosacea, but its specific mechanisms in epidermal innate immunity remain unclear. Isotretinoin is an effective therapy for rosacea, yet its epigenetic mechanism of action is incompletely understood. This study analyzed human rosacea transcriptomic data, established an epidermis-specific Tet2 knockout (TET2eKO) mouse model, and knocked down TET2 in keratinocytes. TET2 and its catalytic product 5hmC were significantly downregulated in human rosacea lesions and in an LL-37-induced rosacea-like mouse model. TET2eKO mice exhibited exacerbated LL-37-induced erythema, telangiectasia, dermal thickening, and immune cell infiltration. Transcriptomic and functional analyses coupled with hMeDIP-qPCR demonstrated that TET2 deficiency led to excessive activation of the JAK2/STAT3 pathway through loss of direct epigenetic constraint, driving the upregulation of pro-inflammatory cytokines and chemokines in keratinocytes. Isotretinoin treatment restored TET2/5hmC levels, suppressed JAK2/STAT3 activation, and mitigated inflammatory responses both in vitro and in vivo. These results indicate that TET2 functions as a key epigenetic brake on cutaneous inflammation by negatively regulating the JAK2/STAT3 pathway in keratinocytes. Consequently, the therapeutic effect of isotretinoin is closely associated with the restoration of TET2 function, providing mechanistic insight into the management of inflammatory dermatoses.
PMID:
42951126
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.
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