Review The JAK/STAT signaling pathway: from bench to clinic, 2021, Hu et al.

[SNT Gatchaman]

The JAK/STAT signaling pathway: from bench to clinic
Hu, Xiaoyi; li, Jing; Fu, Maorong; Zhao, Xia; Wang, Wei

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases.

In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

Link | PDF (Nature Signal Transduction and Targeted Therapy)

 

[SNT Gatchaman]

This is an in-depth review paper. Posting in relation to upcoming trial on Baricitinib in LC, which is a first generation JAK1/JAK2 inhibitor. In addition to the JAK inhibitors, there are sections on STAT inhibitors, including things like resveratrol, curcumin and other high "consumer-availability" but low bio-availability small molecules.

Here's the section on baricitinib, abbreviated for easy reference —

Baricitinib: Baricitinib is a selective oral JAK1 and JAK2 inhibitor [...] Baricitinib achieved efficacy in multiple autoimmune diseases, including RA, lupus erythematosus, juvenile dermatomyositis, atopic dermatitis, and IFN-mediated autoinflammatory disease, it inhibits the worsening of symptoms and reduces inflammation.

Moreover, baricitinib inhibits inflammation via JAK1/2-mediated cytokine signaling. One of the most important effects was the rapid and remarkable inhibition of macrophage production of the cytokines and chemokines critical for inflammation and neutrophil recruitment. A double-blind, randomized, placebo-controlled trial including 1033 hospitalized adults revealed that baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status. Patients with severe COVID-19 had a significant reduction in serum IL-6, IL1β, TNF, increased antibodies against the SARS-CoV-2 spike protein, and rapid recovery of B-cell and T-cell frequencies.

With exposure as many as 5.5 years, baricitinib has an acceptable safety profile. There is no difference in serious adverse effects such as death, adverse events leading to drug discontinuation, MACE, and malignancies. The most frequently reported AE was dose-dependent increased low-density lipoprotein (42.1%), followed by an increased risk of infections, including herpes zoster and TB. Baricitinib should be used with caution in patients with VTE risk factors.