Curcumol inhibits KLF5-dependent angiogenesis by blocking the ROS/ERK signaling in liver sinusoidal endothelial cells

Aims: Liver fibrosis is a difficult problem in the medical field. We previously reported that curcumol, a bioactive substance, may inhibit the pathological angiogenesis of liver sinusoidal endothelial cells (LSECs) and play a good anti-hepatic fibrosis effect. However, the mechanism of curcumol inhibiting angiogenesis in LSEC needs to be further clarified. Here, we focus on how curcumol inhibits LSEC angiogenesis in liver fibrosis.

Materials and methods: Primary rat LSECs were cultured in vitro, and various molecular experiments including Real-Time PCR, western blot, immunofluorescence, tube formation assay and transwell migration assay were used to clarify the potential mechanism of curcumol. Carbon tetrachloride (CCl₄) was applied to create a mouse liver fibrosis model. Blood and livers were taken to elucidate the efficacy of curcumol in vivo.

Key findings: We found that curcumol could effectively inhibit LSEC angiogenesis in vitro. Interestingly, this process may depend on curcumol's inhibition of the expression of transcription factor KLF5. Mice experiment also showed that curcumol could alleviate chronic liver injury by reducing KLF5 expression. In addition, we suggested that curcumol could reduce the production of mitochondrial ROS and improve mitochondrial morphology in LSEC. More importantly, we proved that curcumol could suppress KLF5-mediated LSEC angiogenesis by inhibiting ROS/ERK signaling.

Significance: We suggested that transcription factor KLF5 could be considered as a new target molecule of curcumol in improving liver fibrosis, and pointed out that curcumol targeted ROS/ERK-mediated KLF5 expression could inhibit LSEC angiogenesis. This provided a new theoretical basis for curcumol to ameliorate liver fibrosis.