Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Abstract

Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

Tumor biomarkers for diagnosis, prognosis and targeted therapy

“… 1276 Inhibition of the JAK/STAT signaling pathway has been demonstrated to downregulate cellular proliferation and survival, decrease stem cell properties and inflammatory response, suppress invasion and metastasis, ameliorate immunosuppress in malignant tumors. 1282 Ruxolitinib is a first-in-class, potent, ATP-competitive, and small molecule JAK1/2 inhibitor (IC 50 = 3.3 nM for JAK1, 2.8 nM for JAK2) developed by Incyte Corp. 1283 Following its approval by the FDA for the treatment of diseases, such as multiple sclerosis and vitiligo, the potential of ruxolitinib in cancer therapy has garnered widespread interest. Several clinical trials of ruxolitinib in patients with pancreatic cancer, breast cancer, relapsed or refractory or post myeloproliferative AML, HNSCC, or NSCLC were either terminated or completed with results suggesting insufficient efficacy to justify further investigation.…”

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

“…All in all, targeting the JAK/STAT metabolic pathway in HCC may be a useful therapeutic option, as it involves several oncogenic and progression-promoting mechanisms typical of HCC, such as chronic inflammation (Fibrosis is associated with oncogenesis and the development of HCC [ 324 , 325 ]), altered metabolism (STAT3 activation enhances the Warburg effect by promoting anaerobic glucose metabolism [ 326 ]), and angiogenesis [ 297 , 327 , 328 ].…”

Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments—An Overview

“…This pathway is important for regulating the immune response, hematopoiesis, and hematopoietic stem cell function, and at the hepatic level, it promotes hepatocyte proliferation, regeneration, and gluconeogenesis [ 60 ].…”