TYK2-JAK1

Overview

TYK2-JAK1 refers to a dual-target protein axis involving tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1), two closely related members of the Janus kinase family that mediate cytokine receptor signaling. In biomedical research and drug development, this target is most often discussed in the context of small-molecule inhibitors designed to modulate inflammatory and immune pathways by suppressing downstream signaling through STAT proteins and related networks.

Because TYK2 and JAK1 participate in overlapping cytokine-driven pathways, they are relevant to diseases characterized by immune dysregulation, including psoriasis, dermatomyositis, and other inflammatory disorders. Pharmacologic inhibition of this axis is intended to reduce pathological cytokine signaling while preserving enough immune function for clinical tolerability. Recent studies have also linked JAK-family signaling to broader pathway interactions such as mTORC1/2 and JAK2/STAT3 signaling, underscoring the network-level effects of targeting TYK2-JAK1 in inflammatory and proliferative disease settings.

Focus of Latest Publications

Recent publications on TYK2-JAK1 have focused largely on its role as a therapeutic target in inflammatory and immune-mediated diseases, with several studies evaluating selective inhibition in clinical or translational settings. Brepocitinib, described as a first-in-class oral selective TYK2-JAK1 inhibitor, was tested in a phase 3 trial in dermatomyositis, reflecting ongoing interest in cytokine-signaling blockade for this condition. In psoriasis, TYK2 and IL-23 pathway therapies were examined alongside transcriptomic and metabolomic profiling, with the study proposing that TYK2 inhibition may have broader effects beyond skin disease, including potential associations with depressive symptoms and inflammatory mediators such as IL-6 and tryptophan metabolism.

Other recent work has explored JAK1-directed inhibition in skin and ocular disease models. In inflammatory skin diseases, a pH-responsive hydrogel was used to co-deliver CCR7-targeting siRNA and the JAK1 inhibitor upadacitinib, with the combined approach reducing keratinocyte proliferation, inducing apoptosis, and downregulating JAK-STAT and PI3K/AKT/mTOR pathway activity in vitro. In mouse models of psoriasis and atopic dermatitis, this strategy improved skin lesions, restored barrier function, reduced hyperplasia and immune-cell infiltration, and lowered systemic inflammatory markers, with mechanistic effects linked to suppression of CCR7, JAK1, STAT3, and mTOR. In retinal pigment epithelium transplantation, paired pre- and post-transplant immunoprofiling identified an IFN-γ-JAK1 axis that promoted an immunogenic state in stem-cell-derived RPE; brief ex vivo conditioning with ruxolitinib reduced HLA expression and antigen-presentation features, and conditioned grafts showed improved survival and visual outcomes in humanized models.

TYK2-JAK1 has also been studied in broader immunology and oncology contexts. A post hoc analysis of the PAISLEY SLE phase 2 trial examined deucravacitinib to better understand the mechanism of TYK2 inhibition in systemic lupus erythematosus. In colorectal cancer, filgotinib, a selective JAK1 inhibitor, was investigated for anti-tumor activity, with the study title indicating induction of apoptosis through activation of the p53 signaling pathway, although the abstract provided only the rationale and did not detail results. Across these publications, TYK2-JAK1-related inhibition is being explored as a means to modulate cytokine signaling, immune activation, and downstream inflammatory or survival pathways in diverse disease settings.

Key Publications

NEWJun Filgotinib induces apoptosis in colorectal cancer cells by activating the p53 signaling pathway. (Molecular biology reports, 2026, PMID 42364020): "Filgotinib is a selective JAK1 inhibitor approved for the treatment of inflammatory diseases."
NEWJun Paired pre- and post-transplant human immunoprofiling identifies an IFN-γ-JAK1 axis limiting stem-cell-derived RPE engraftment. (Cell stem cell, 2026, PMID 42309064): "We identify a Th1-skewed, IFN-γ-rich immune milieu across the circulation and eye and show that IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE, marked by increased HLA expression and antigen presentation features."
Jun A combination therapy strategy: precision co-targeting of CCR7 and JAK1 with a smart hydrogel for inflammatory skin diseases. (Journal of nanobiotechnology, 2026, PMID 42237357): "The therapeutic effects were mechanistically linked to synergistic downregulation of CCR7, JAK1, STAT3, and mTOR in lesions, and reduced populations of aberrantly activated T cells, neutrophils, and dendritic cells in the spleen."
May Clinical benefit and predictors of response to momelotinib after ruxolitinib failure: A cooperative real-world study. (Cancer, 2026, PMID 42118670): "Momelotinib, a JAK1/JAK2/ACVR1 inhibitor, is approved for treating myelofibrosis with splenomegaly, symptoms, and moderate-to-severe anemia."
May Whole blood transcriptome profiling in patients treated with deucravacitinib and novel mechanistic insights into TYK2 inhibition in lupus: results from a post hoc analysis of the PAISLEY SLE phase 2 trial. (Annals of the rheumatic diseases, 2026, PMID 42115051): "To further understand the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY SLE trial."
May A Phase 3 Trial of Brepocitinib in Dermatomyositis. (The New England journal of medicine, 2026, PMID 41910335): "Brepocitinib is a first-in-class, oral, selective TYK2-JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis."
Jun TYK2 and IL-23 Pathway Therapies in Psoriasis: Associations With IL-6, Tryptophan Metabolism, and Depressive Symptoms. (International journal of dermatology, 2026, PMID 41524454): "This study, integrating clinical assessments with transcriptomic and metabolomic analyses, hypothesizes that TYK2 (tyrosine kinase 2) inhibitors possess a dual therapeutic potential to simultaneously address both dermatological manifestations of psoriasis and the frequently accompanied depressive symptoms."