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Albiflorin Discovered from Paeoniae Rubra Radix Attenuates Liver Fibrosis and Inflammation via Regulating CXCL12/CXCR4 Axis

ABSTRACT: Liver fibrosis, a common pathological feature of chronic liver injury, faces a lack of effective treatment methods. Albiflorin (ALB), a pinane-type monoterpene compound isolated from the medicinal and edible plant Paeonia lactiflora Pall, has demonstrated a variety of biological activities. Here, we reported on the hepatoprotection and potential mechanisms of ALB against liver fibrosis. The results indicated that ALB significantly alleviated the histological damage and collagen deposition caused by CCl4-induced liver fibrosis and led to a reduction in serum levels of ALT, AST, CRE, and BUN. Meanwhile, ALB downregulated the expression of liver fibrosis markers (α-SMA and Collagen I) and decreased inflammatory cytokines (IL-1β, IL-6, TNF-α, and NLRP3). According to RNA-sequencing analysis, the CXCL12/CXCR4 axis was identified as a potential signaling pathway for ALB's action against liver fibrosis. Further mechanistic data revealed that ALB exerts anti-inflammatory and antifibrotic effects through the JAK1/STAT3 and p38 MAPK pathways mediated by the CXCL12/CXCR4 axis. Notably, treatment with AMD3100 diminished the hepatoprotective effect of ALB on CCl4-induced liver fibrosis. Furthermore, we found that the combination of ALB with metformin (MET) exhibited a significant synergistic effect in the treatment of liver fibrosis, with the CXCL12/CXCR4 axis playing a crucial role in this process. Thus, the findings of this study provided theoretical data support and suggested a new possible treatment strategy for liver fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282681 | GEO | 2025/05/22

REPOSITORIES: GEO

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Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

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Albiflorin Discovered from Paeoniae Rubra Radix Attenuates Liver Fibrosis and Inflammation via Regulating CXCL12/CXCR4 Axis

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