MDI1228, a topical pan-JAK inhibitor, disrupts dermal fibroblast-T cell chemokine crosstalk to resolve allergic contact and atopic dermatitis.

Introduction: Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are driven by distinct T cell programs, and safe long-term topical therapies remain limited. Dermal fibroblasts (dFBs) have emerged as active immunomodulators, but whether they can be therapeutically targeted remains unexplored. Methods: Here we developed MDI1228, a novel topical pan‑JAK inhibitor with nanomolar potency against JAK1/2/3/TYK2 (IC₅₀ 0.11-0.85 nM) and high selectivity. MDI1228 was evaluated in DNFB‑induced ACD and MC903‑induced AD mouse models, as well as in primary mouse and human cell‑based assays. Results: Topical MDI1228 ameliorated both ACD and AD in mice, reducing T cell infiltration and cytokine production. Mechanistically, MDI1228 not only directly inhibited T cell activation and cytokine production but also disrupted fibroblast‑T cell crosstalk by reducing dFB‑derived chemokine expression. Single‑cell transcriptomics identified dFBs as the primary source of CXCL9/10 in ACD and CCL2 in AD. Conditioned medium and neutralization experiments demonstrated that CXCL9/10‑CXCR3 and CCL2‑CCR2 signaling axes contribute to T cell polarization in a context‑dependent manner. Compared with glucocorticoids, prolonged topical application of MDI1228 showed minimal systemic toxicity and preserved tissue homeostasis. Discussion: These findings identify dFBs as a central therapeutic node and demonstrate that MDI1228, by directly targeting T cells and disrupting dFB‑derived chemokine axes via JAK inhibition, offers a potent and safe topical treatment for both ACD and AD.