Hepatocellular carcinoma (HCC) is a frequent malignancy that has a high death rate and a high rate of recurrence following surgery, owing to insufficient surgical resection. Furthermore, HCC is prone to peritoneal metastasis (HCC-PM), resulting in a significant number of tiny cancer lesions, making surgical removal more challenging. As a potential imaging target, FGFR4 is highly expressed in tumors, especially in HCC, but is less expressed in the normal liver. In this study, we used computational simulation approaches to develop peptide I0 derived from FGF19, a particular ligand of FGFR4, and labeled it with the NIRF dye, MPA, for HCC detection. In surgical navigation, the TBR was 9.31 ± 1.36 and 8.57 ± 1.15 in HepG2 in situ tumor and HCC-PM models, respectively, indicating considerable tumor uptake. As a result, peptide I0 is an excellent clinical diagnostic reagent for HCC, as well as a tool for surgically resecting HCC peritoneal metastases.
Introduction and objectives The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis. The beneficial effects of fibroblast growth factor (FGF) 19 on liver fibrosis were recently reported. The S. miltiorrhiza as well as S. miltiorrhiza derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood. We aimed to investigate the bioactive compounds derived from S. miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19. Materials and methods FGF19 level in culture media was determined by enzyme-linked immunosorbent assay. Cell proliferation was measured by Cell Counting Kit-8 assay. Further, mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting, respectively. Knocking down of FGF receptor 4 (FGFR4) by transfection with siRNA was used to confirm the role of FGF19/FGFR4 signaling. Results Using the human HSC cell line LX-2, we screened several natural products and found that bioactive compounds isolated from Salvia miltiorrhiza , particularly salvianolic acid B, strongly upregulated FGF19 secretion by LX-2 cells. We further showed that salvianolic acid B inhibited lipopolysaccharide (LPS)-induced HSC proliferation and activation. LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4. Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4. Finally, FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model. Conclusions Salvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19/FGFR4 signaling.
Chronic alcohol consumption disrupts gut microbiota and metabolic processes, leading to the transfer of microbial toxins from the intestines to the liver and accelerating the progression of alcoholic liver fibrosis (ALF). However, no effective drugs currently exist to treat ALF. Safflower polysaccharide (SPS), a natural compound extracted from safflower, has garnered significant attention in recent years for its potential clinical applications in treating liver-related diseases. However, the efficacy of SPS in improving ALF and its underlying mechanisms remain unclear. Research indicates that SPS alleviates liver injury in ALF mice by modulating inflammation and fibrosis mechanisms through the gut-liver axis and inhibiting hepatic stellate cell activation. SPS promotes the proliferation of beneficial bacteria, improves gut microbiota composition—including Lactobacillus and Bifidobacterium—and alters bile acid pool composition and its metabolites. Notably, the protective effect of SPS in ALF mice is attenuated by FXR inhibition. In vitro experiments confirmed that SPS effectively activates the FXR/FGFR4/FGF15 signaling pathway, counteracting the inhibitory effects of alcohol or specific bile acids on FXR activity. Immunofluorescence and Western blot analyses further confirmed that SPS enhances FXR activity by promoting its expression. These findings reveal a dual mechanism of action for SPS through regulating gut microbiota and bile acid metabolism, providing a theoretical basis for FXR-targeted therapy in ALF and suggesting that the FXR/FGFR4/FGF15 pathway may represent a potential mechanism of action.
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