Page 13 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Progress in the research of pathology and therapy in liver fibrosis

antigens are then presented to T lymphocytes, facilitating downregulates HSC activation and profibrogenic trans-
immune recognition, response, and regulation. 9-11 In the differentiation into myofibroblasts, 22-25 suppresses hepatic
context of liver injury, monocytes infiltrate and become angiogenesis, and reduces hepatic progenitor viability, 27-29
26
activated through specific mechanisms. Once activated, and finally mitigating fibrogenesis. In general, since most
they secrete a substantial amount of cytokines, including ligands influence hepatic physiological and pathological
transforming growth factor beta (TGF-β), tumor necrosis processes, exploring their molecular mechanisms is crucial
factor-alpha (TNF-α), C-C motif chemokine ligand 5 for liver fibrosis research.
(CCL5), platelet-derived growth factor BB (PDGF-BB), Most studies aim to uncover the molecular mechanism
interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), which underlying the onset and development of liver fibrosis,
promote HSC activation and transformation through restore the resting state of HSCs, and reduce ECM to delay
multiple pathways. 12,13 or reverse disease progression. Some of these findings have
During the repair of chronic liver injury, the already advanced to pre-clinical trials. Therefore, this review
uncontrolled proliferation of activated HSCs causes the aims to elucidate the molecular mechanisms driving liver
release of numerous inflammatory factors and paracrine fibrosis progression and current diagnostic approaches,
effects, playing a very important role in the development combined with relevant modern and traditional anti-
of liver fibrosis. HSC activation and proliferation involve fibrotic therapies, which provides a rationale for the drug
multiple signaling pathways, mainly the TGF-β1 and development of liver fibrosis (Figure 1).
platelet-derived growth factor (PDGF) pathways. TGF-β1 2. Clinical assessment of liver fibrosis
is the most potent cytokine to induce HSC activation
through the Smad2/3-dependent pathway. 14,15 PDGF is 2.1. Pathological assessment of liver fibrosis
known as the strongest mitogen for HSCs both in vitro There are numerous factors that can lead to chronic
and in vivo. Upon binding to its receptor (PDGFR), PDGF liver injury, including hepatitis virus infection, non-
activates the Ras-mitogen-activated protein kinase (Ras- alcoholic fatty liver disease (NAFLD), excessive alcohol
MAPK) pathway and the phosphoinositide-3-kinase consumption, autoimmune hepatitis, cholestatic liver
(PI3K)-protein kinase B (Akt/PKB) pathway, eventually disease, and drug-induced hepatotoxicity. Liver fibrosis,
stimulating protein kinase C (PKC) family members, characterized by excessive activation of HSCs and altered
which lead to the HSC reproduction and motility. 16 ECM composition, is a wound-healing response to chronic
Ligand-dependent signaling also plays an important liver injury that ultimately disrupts normal liver structure.
role in liver pathophysiology. Highly conserved genes Histopathology features of liver fibrosis vary by etiology. For
encode various membrane surface receptors such as instance, chronic viral hepatitis induces portal expansion
Wnt, Notch, and Hedgehog (Hh), which regulate ligand- with periportal fibrosis, which then progresses to septal
dependent signaling pathways. Wnt signaling components fibrosis and ultimately cirrhosis. In contrast, fibrosis in
are upregulated in response to liver fibrogenesis and NAFLD or alcoholic hepatitis is marked by centrilobular
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hepatitis. 17,18 In addition, Wnt1-inducible signaling perivenular and sinusoidal fibrosis. Cholestatic liver
pathway protein 1 has been demonstrated to mediate the cirrhosis, on the other hand, is characterized by bile duct
canonical Wnt signaling pathway, playing an important role loss and concentric periductal fibrosis. 37
in hepatic inflammation and the progression of obesity- All chronic liver diseases have the potential to progress
associated liver fibrosis. Disruption of myofibroblast- to advanced fibrosis, cirrhosis, and even hepatocellular
19
specific Notch signaling not only inhibits primary HSC carcinoma (HCC), which result in poor prognosis and
activation in vitro but also aggravates BCL2 associated X high mortality. Hence, a precise assessment of liver fibrosis
(BAX)-mediated apoptosis of myofibroblasts, accompanied is urgently needed in the clinical management of chronic
by the overexpression of nerve growth factor receptor and liver disease. Several histological staging systems have been
Septin4. In addition, the non-canonical Notch ligand proposed, including the Knodell, Scheuer, Batts-Ludwig,
20
delta-like non-canonical Notch ligand 1 plays a crucial role METAVIR, and Ishak systems. 38,39 While these systems
in ECM remodeling by reducing ECM deposition through differ slightly, they share a common principle that fibrosis
the downregulation of ECM constituents expression and begins from the portal tracts, extends to adjacent areas,
an increased matrix metalloproteinases/tissue inhibitor disrupts hepatic lobular architecture, and ultimately leads
of metalloproteinases (MMPs/TIMPs) ratio. Previous to cirrhosis. The Ishak system includes two additional
21
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studies have demonstrated that inhibition of Sonic Hh stages of fibrosis in detail compared to other systems,
and other Hh pathway components, such as Smoothened which decreases its clinical utility and convenience. The
(SMO) and the transcription factor of Glioblastoma 2, four-category fibrosis classification, such as the METAVIR

Volume 9 Issue 3 (2025) 5 doi: 10.36922/ejmo.8125