Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by many cytokines and growth factors and plays a key role in cell survival, proliferation, and differentiation. STAT3 activation is detected virtually in all rodent models of liver injury and in human liver diseases. In this review, we highlight recent advances of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis. The cytokines and small molecules that activate STAT3 in hepatocytes may have therapeutic benefits to treat acute liver injury, fatty liver disease, and alcoholic hepatitis, while blockage of STAT3 may have a therapeutic potential to prevent and treat liver cancer.

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

“…In Kupffer cells, the transient activation of STAT3 by IL-6 is proinflammatory, promoting HSC survival and proliferation (10). The activation of STAT3 in HSCs by IL-6 or leptin stimulates HSC survival, proliferation, and activation (8,16,17). Nevertheless, the exact mechanisms of IL-6/STAT3 in HSC during liver fibrogenesis remain to be determined.…”

“…Furthermore, SHP-1 phosphatase-directed therapy (e.g., SC-1) might be a previously unidentified strategy for the discovery of antifibrotic drugs. STAT3 activation has been detected in several human liver diseases, and STAT3 signaling is involved in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis (8,9). The role of STAT3 in liver inflammation and fibrosis is cell type-specific and model-dependent.…”

“…The role of STAT3 in liver inflammation and fibrosis is cell type-specific and model-dependent. STAT3 activation in hepatocytes induces acute phase responses, promoting liver regeneration, hepatocyte survival, and ameliorating fatty liver (8,13). In hepatocyte-specific STAT3 knockout mice, CCl 4 injection induced greater liver damage than wild-type mice (14).…”

“…However, the underlying mechanisms of the antifibrogenic effects remain unclear. The signal transducer and activator of transcription 3 (STAT3) is a transcription factor associated with liver injury, inflammation, and regeneration (8,9). Several studies have shown that interleukin-6 (IL-6) activates STAT3 in HSCs and promotes their survival, proliferation, and activation, thus contributing to liver fibrogenesis (8,10).…”

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

“…Most of the predominant risk factors are well known and include hepatitis B and C viral infections, abusive alcohol consumption, autoimmune hepatitis, metabolic dysfunction, and genetic determinants as for hemochromatosis and Alpha 1-antitrypsin deficiency (1,2). Regardless of the etiology, chronic tissue injury and inflammation are considered drivers of liver disease progression from fatty liver disease and fibrosis to hepatocellular carcinoma (HCC) 1 (3).…”