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Here, we selectively activated G\n                    <jats:sub>12<\/jats:sub>\n                    signaling in keratinocytes using a chemogenetic strategy. Activation of a G\n                    <jats:sub>12<\/jats:sub>\n                    \u2010coupled designer receptor (G\n                    <jats:sub>12<\/jats:sub>\n                    D) in mouse epithelial cells induced pronounced epidermal thickening while preserving stratified architecture and avoiding overt inflammatory skin changes. This thickening was accompanied by increased Ki67\u2010positive cells, expansion of keratin 10\u2010 and filaggrin\u2010positive layers, and transcriptomic upregulation of genes related to keratinocyte differentiation, keratinization, and epidermal barrier function. Functionally, G\n                    <jats:sub>12<\/jats:sub>\n                    D activation strengthened barrier performance, as shown by blunted transepidermal water loss responses to mechanical barrier disruption. Although alarmin\u2010related genes were upregulated, cytokine analyses indicated only modest inflammatory changes. Pharmacologic inhibition of TYK2 (deucravacitinib) partially reduced G\n                    <jats:sub>12<\/jats:sub>\n                    D\u2010driven epidermal thickening, whereas mTORC1 inhibition (rapamycin) produced a stronger suppressive effect, suggesting that the mTORC1\u2010dependent keratinocyte response is a major driver of this phenotype, with a moderate TYK2\u2010dependent component. Together, these findings identify epidermal G\n                    <jats:sub>12<\/jats:sub>\n                    signaling as a regulator that promotes \u201cnon\u2010pathological\u201d epidermal thickening coupled to enhanced barrier function, supporting G\n                    <jats:sub>12<\/jats:sub>\n                    \u2010coupled GPCRs as potential therapeutic entry points for barrier\u2010compromised skin disorders.\n                  <\/jats:p>","DOI":"10.1096\/fba.2026-00042","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T14:14:18Z","timestamp":1785507258000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemogenetic Activation of\n                    <scp>\n                      G\n                      <sub>12<\/sub>\n                    <\/scp>\n                    Signaling Thickens the Epidermis With Enhanced Barrier 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