Signal transducer and activator of transcription 1 and signal transducer and activator of transcription 3 (STAT1/3)

STAT1/3 refers to the dual signaling axis or combined targeting of Signal Transducer and Activator of Transcription 1 (STAT1) and Signal Transducer and Activator of Transcription 3 (STAT3). These proteins are latent cytoplasmic transcription factors that, upon activation by Janus kinases (JAKs), undergo tyrosine phosphorylation, form dimers (including STAT1:STAT3 heterodimers), and translocate to the nucleus to regulate gene expression [1, 2, 8]. While STAT1 and STAT3 often exhibit antagonistic roles in cancer—with STAT1 generally acting as a tumor suppressor and STAT3 as an oncogene promoting survival and immune evasion—they frequently cooperate in driving inflammatory responses [12, 16, 17]. Dysregulation of the STAT1/3 pathway is a hallmark of various malignancies and chronic inflammatory conditions such as rheumatoid arthritis and gout [11, 18]. Therapeutic strategies targeting STAT1/3 typically involve the use of JAK inhibitors to block upstream phosphorylation or experimental direct inhibitors that target their SH2 domains to prevent dimerization [4, 5, 18]. Because of their central role in immune homeostasis, targeting STAT1/3 requires careful management to balance therapeutic efficacy with the risk of systemic immunosuppression and infection [18, 19].

Other names

STAT1/STAT3Signal transducer and activator of transcription 1/3STAT1; STAT3pSTAT1/3STAT1:STAT3 heterodimer

Janus kinase inhibition (indirect), inhibition of tyrosine phosphorylation, blocking of SH2-mediated dimerization, and prevention of nuclear translocation and DNA binding of STAT dimers.