Roseotoxin B alleviates cholestatic liver fibrosis through inhibiting PDGF-B/PDGFR-β pathway in hepatic stellate cells

Abstract

Identifying effective anti-fibrotic therapies is a major clinical need that remains unmet. In the present study, roseotoxin B was shown to possess an improving effect on cholestatic liver fibrosis in bile duct-ligated mice, as proved by histochemical and immunohistochemical staining, hepatic biochemical parameters, and TUNEL apoptotic cell detection in tissue sections. Using cellular thermal shift assay, computational molecular docking, microscale thermophoresis technology, and surface plasmon resonance biosensor, we confirmed that PDGFR-β was a direct target of roseotoxin B in fibrotic livers. Of note, human tissue microarrays detected pathologically high expression of p-PDGFR-β in liver samples of~80% of patients with liver fibrosis and cirrhosis. PDGF-B/PDGFR-β pathway promotes transdifferentiation and excessive proliferation of hepatic stellate cells (HSCs), which is a very crucial driver for liver fibrosis. Meaningfully, roseotoxin B blocked the formation of PDGF-BB/PDGFR-ββ complex by targeting the D2 domain of PDGFR-β, thereby inhibiting the PDGF-B/PDGFR-β pathway in HSCs. In summary, our study provided roseotoxin B as a unique candidate agent for the treatment of liver fibrosis.

Function of TREM1 and TREM2 in Liver-Related Diseases

“…However, when there is chronic liver injury, chronic inflammation and fibrosis lead to pathological conditions [29,95]. HSCs play an important role in fibrosis process, which can be activated by IL-6, transforming growth factor-β (TGF-β), and platelet-derived growth factor [96][97][98]. After liver injury, KCs not only produce pro-inflammatory factors to activate HSCs but also recruit CCR2+/Ly-6Chi monocytes into injured liver to sustain activation of HSCs [99].…”

Pathogenesis of Liver Fibrosis and Its TCM Therapeutic Perspectives

“…PDGFR- β expression shows an upregulation trend with HSC activation and PDGFR- β acts as the most promising proliferation mediator for HSC, inducing further HSC proliferation [ 113 ]. Liver sinusoidal endothelial cell vascularization increases liver permeability due to loss of PDGFR- β activity [ 30 ], and most liver samples from patients with liver fibrosis show increased levels of PDGFR- β expression, while PDGFR- β is a key pathway to induce HSC activation and proliferation [ 114 ].…”

Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment

“…However, the absence of FGF1 and FGF2 did not impair the total number of HSCs and their migration into the areas of injury, but overproduction of matrix components, especially collagen α1(I), by those, and therefore excessive fibrous tissue accumulation. The probable explanation is that FGF1 and FGF2 are not essential activating ligands for proliferation and migration of activated HSCs in vivo, but the important ones for fibrosis progression [43].…”

“…Moreover, proteins enriched in TGFR signaling involve Src, cAMP response element-binding protein (CREBP) and others, and some of them belong to EGFR signaling, indicating the crosstalk between these pathways [51]. Additionally, TGF-β1 also mediates the role of FGF1 and FGF2 in the deposition of ECM, or FGF1 and FGF2 mediate the TGF-β activity, or both factors play independent roles through convergent signaling pathways in vivo [43].…”