Page 17 - EJMO-9-3

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

and liver function improvement, as indicated by decreased reported as an adverse effect of FXR agonist therapy.
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levels of TGF-β1, IL-6, and endothelin-1 at the end of Dyslipidemia is another main side effect of OCA, though
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the observation period, whereas only 4.1% in the control the increase in mean low-density lipoprotein levels
group (74 patients receiving the standard of care regimen) induced by OCA in NASH patients can be mitigated with
showed similar improvement. The evidence shown atorvastatin (NCT02633956). 91
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by previous studies clearly demonstrates that PFD is a PPAR-α, PPAR-γ, and PPAR-β/δ belong to the PPAR
promising anti-fibrotic drug in a cirrhotic population with family, which is responsible for the lipid metabolism
mild side effects, such as gastrointestinal discomfort. in the liver. Modulating PPAR activity can ameliorate
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3.3. Molecularly targeted agents for liver fibrosis inflammatory responses and fibrogenesis in the liver.
In addition, PPAR-γ plays a key role in the negative
Targeted anti-fibrotic therapy has entered a brand-new era. regulation of HSC activation and trans-differentiation.
The Farnesoid-X receptor (FXR) and PPAR are two vital A meta-analysis indicated that the anti-diabetic drug
transcriptional regulators of key metabolic processes in the pioglitazone, a selective PPAR-γ agonist, could to some
liver, including inflammation, fibrogenesis, proliferation, extent reverse fibrosis at any stage in patients with
apoptosis as well as hepatic lipid and glucose metabolism. NASH, regardless of diabetes status. Saroglitazar, a
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Therefore, drugs directly targeting FXR and PPAR have led dual PPARα/γ agonist, effectively induced the resolution
to important breakthroughs in the treatment of NAFLD, of histological responses in diet-induced NASH mouse
NASH, and primary biliary cholangitis (PBC). models. In a pilot study of saroglitazar therapy in
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Obeticholic acid (OCA) is a potent, specific FXR humans (NCT03112681), a daily dosage of 2 mg was
agonist that was first approved for the treatment of PBC. found to decrease the disease activity marker alkaline
Findings from a series of clinical trials (NCT01473524, phosphatase in patients with PBC. However, higher drug
NCT02177136) with long-period OCA treatment provided intake led to potential liver injury, as indicated by elevated
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substantial evidence for its long-term efficacy in the PBC liver enzymes. The pan-PPAR agonist lanifibranor has
population. Patients in the OCA group had lower alkaline been a leading drug candidate for NASH treatment. It
phosphatase and total bilirubin levels from baseline showed outstanding performance in meliorating the
compared to the placebo group. 81-83 Recently, histological severity of steatosis, inflammation, fibrosis, and even
results from a sub-trial of the PBC OCA International portal hypertension in pre-clinical models. 96-98 Moreover,
Study of Efficacy (POISE, NCT01473524) revealed great at a high dose (1200 mg), lanifibranor eased the active
improvements or stabilization in hepatic morphometric stage of steatohepatitis in NASH without deteriorating
features, including ductular injury, fibrosis stage, and fibrosis (NCT03008070). 99
collagen production, following OCA administration.
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For NASH, a multicenter, randomized, placebo-controlled 3.4. Targeted drug delivery system for liver fibrosis
Phase 3 trial (REGENERATE) treated NASH patients Targeted drug delivery systems have important potential
with fibrosis stage F2 – F3 with OCA. The 18-month clinical applications with the advantages of prolonged
midterm analysis in the REGENERATE trial showed residence time and improved specificity of drug delivery.
that OCA treatment ameliorated fibrosis and NASH in A study found that poly (lactide-co-glycolide) NPs
a dose-dependent manner, with greater histological and loaded with sorafenib increased blood residence time of
laboratory improvements observed in the OCA 25 mg sorafenib and decreased fibrotic accumulation of alpha-
group. Nonetheless, analyses of diverse non-invasive smooth muscle actin (α-SMA) and collagen, as well as
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tests, including biochemical and imaging examinations, microvascular density in the CCl4-treated fibrotic liver.
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echoed the results of the previous histological study. It is At present, targeted delivery systems for anti-fibrotic drugs
worth noting that some non-invasive evaluations showed have advanced to dual- or multi-functional approaches due
improvements in OCA-treated patients with fibrosis to continuous technological and equipment developments,
stabilization (NCT02548351). Cilofexor (GS-9674), the including NP and liposome delivery systems, HSC surface
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second generation of FXR agonists, was well tolerated and membrane-specific receptor systems, and nano-micelle
significantly improved liver biomarkers and radiological drug carrier systems. For instance, the intrinsic chemico-
manifestations of cholestasis in primary sclerosing physical properties of titanium dioxide (TiO ) NPs and
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cholangitis patients (NCT02854605). 87 Vonafexor silicon dioxide (SiO ) NPs were first reported to inhibit liver
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(EYP001), another novel synthetic FXR agonist, showed fibrosis through multiple mechanisms, such as restoring
anti-fibrotic effects in NASH patients, with improvements HSCs from the myofibroblast-like state, accelerating ECM
observed in MRI findings and serum indicators of liver and degradation, and even inhibiting gene expression related
renal function (NCT03812029). Pruritus was frequently to HSC adhesion and migration. When sorafenib was
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Volume 9 Issue 3 (2025) 9 doi: 10.36922/ejmo.8125