Ritlecitinib’s mechanism of action

Ritlecitinib (Ritlecitinib) irreversibly inhibits Janus kinase 3 (JAK3) and tyrosine kinases expressed in the hepatocellular carcinoma (TEC) kinase family by blocking the adenosine triphosphate (ATP) binding site. In vitro, ritexitinib inhibits cytokine-induced STAT phosphorylation mediated by JAK3-dependent receptors and signaling of immune receptors that are dependent on members of the TEC kinase family. Although JAK inhibitors (such as ritixitinib) may inhibit the inflammatory pathways activated in alopecia areata, their exact mechanisms of action have not been fully elucidated.

Alopecia areata is an autoimmune disease that causes hair loss primarily on the scalp as well as on the face and other areas. Under normal circumstances, hair follicles are immune-privileged sites characterized by the presence of well-suppressed natural killer cells. However, disruption of this system can lead to loss of immune privilege and cause alopecia areata. Genome-wide association studies have linked overexpression of UL16-binding protein 3 (ULBP3), a protein that binds to natural killer cell receptors, to the pathogenesis of alopecia areata. Overexpression of ULBP3 promotes cytotoxic cluster differentiation 8-positive (CD8+) NK group 2D-positive (NKG2D+) T cells to attack hair follicles, leading to hair follicle dystrophy. CD8+ NKG2D+ T cells promote hair follicle inflammation through interferon-γ (IFN-γ) and interleukin-15 (IL-15) signaling pathways, thereby activating the Janus kinase (Janus signal transducer and activator of transcription (STAT) molecular pathway. Therefore, JAK inhibitors have been proposed for the treatment of alopecia areata.