Page 34 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Role of common CXC chemokines in NAFLD

semaglutide, pancreatic glucagon-like peptide 1 receptor mitogen-activated protein kinase (MAPK) signaling cascade
agonists, were each shown to significantly improve the that induces CXCL10 consists of mediator modules of
histologic progression of NASH in two independent Phase MLK3, MKK3/6, and p38, and it was demonstrated that in
2 clinical trials, with significant improvements in hepatic lipotoxic hepatocytes, MLK3 activates the MAPK signaling
steatosis and hepatocellular ballooning observed in cascade, leading to activated phosphorylation of STAT1 and
patients treated with liraglutide. 75,76 Pegozafermin, a novel transcriptional upregulation of CXCL10, MLK3/STAT1
glycopegylated version of human fibroblast growth factor repression or deletion of a shared STAT1 binding site within
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21, significantly improves liver fibrosis in patients with the CXCL10 promoter attenuates promoter activation.
NASH through modulation of lipid and glucose metabolism Targeting this therapeutically might lead to a decrease in
as well as adiponectin levels and does not worsen NASH. CXCL10 expression and prevent NASH progression. Wada
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Low-molecular-weight fucoidan and high-stability et al. found that insulin resistance led to elevated expression
fucoxanthin (LMF-HSFx) is a seaweed extract, which can of CXCL10 mRNA in monocytes only when accompanied
regulate lipid and glycogen metabolism, attenuate insulin by stimulation of bacterial-associated TLR2, and thus strict
resistance, and inhibit hepatic inflammatory responses control of insulin resistance and intestinal barrier function
through the adiponectin-adipoR1/2 and SIRI-PGC-1 could inhibit the progression of NAFL to NASH to some
pathways in adipocytes and hepatocytes. Saroglitazar, extent. Recent research focusing on CXCL10 as a treatment
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a PPARα/γ dual agonist, has been observed to improve target for NAFLD has been on the rise; for example, activation
the histological features of NASH in animal studies. of silencing information regulator 1 (SIRT1) and adenosine
A randomized controlled clinical trial based on these A2a receptor (A2aR), 87,88 an increase in the expression level
findings showed that saroglitazar significantly improved of microRNA-223, and rilpivirine through the MAP kinase
ALT, LDL cholesterol, insulin resistance, and atherogenic and PI3K/mTOR pathways can inhibit the expression level of
dyslipidemia in patients with NAFLD. Cenicriviroc is CXCL10 and reduce liver inflammatory injury. 89
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an oral chemokine receptor Type 2 and 5 (CCR2/CCR5)
antagonist that has antifibrotic activity through inhibition 6. Summary and prospects
of monocyte-derived megakaryocyte infiltration. 80 There is still a lack of effective drugs to treat NAFLD, and
Experiments directly using CXCL1/CXCL2/CXCL8/ invasive liver tissue biopsy remains the “gold standard” for
CXCL10 antagonists to intervene in NAFLD therapy diagnosis of NAFLD; therefore, it is necessary to find new
are still lacking, but changes in several CXC chemokines treatments and biomarkers that can be used to diagnose
can be observed in experiments intervening in NAFLD NAFLD. CXC family chemokines have been implicated
therapy by other natural products and drugs. Studies have in the pathogenesis of NAFLD, among which CXCL1,
shown that valine and isoleucine can significantly reduce CXCL2, CXCL8, and CXCL10 have been subjected to more
inflammation within the liver during the development of extensive discussion over the past few years due to their
NAFLD by inhibiting the chemokine proteins KC/CXCL1, close association with NAFLD, and the baseline expression
MCP-1/CCL2, MIP-2/CXCL2, and their pathways. levels of these four CXC family chemokines under normal
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Hepatocyte growth factor (HGF), a versatile protein, plays a circumstances are significantly higher than the levels when
role in both anti-inflammatory and anti-fibrotic responses, NAFLD is compounded by liver injury and inflammation.
and it has been shown that recombinant HGF inhibits Hence, blocking or inhibiting CXC chemokines and their
macrophage infiltration and upregulation of chemokine receptor signaling may provide a more specific therapeutic
CXCL1 thereby slowing down the development of NASH. strategy for NAFLD. However, the mechanisms of these
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The administration of exogenous HGF may be a favorable four chemokines in the development of NAFLD still need
option for the treatment of NAFLD. Chronic administration further exploration. In addition, CXCL8 and CXCL10 have
of physiologic concentrations of indole in vivo has anti- been suggested to be potential non-invasive biomarkers for
inflammatory and hepatoprotective effects, a process that the prediction of NASH, which also need to be validated
is accompanied by a decrease in CXCL2 expression. through further clinical trials.
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Zaluzanic C has antioxidant and anti-inflammatory effects Acknowledgments
on NAFLD, and it inhibits lipopolysaccharide (LPS)-
induced mitochondrial ROS (mtROS) production and None.
reduces mRNA levels of pro-inflammatory factors and
chemokines (CXCL2). Under lipotoxic stress, hepatocytes Funding
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induce high levels of macrophage CXCL10 production and This work was supported by Zhejiang Scientific
release CXCL10-rich extracellular vesicles through a mixed Research Foundation of Traditional Chinese Medicine
spectrum kinase 3 (MLK3)-dependent mechanism. The (NO.2022ZB106).

Volume 9 Issue 3 (2025) 26 doi: 10.36922/ejmo.8383