Regulation of endoplasmic reticulum stress and liver injury by hydroxysafflor yellow a through mir-222-3p-pten-wnt axis

Eur J Pharmacol. 2025 Sep 15;1003:177949. doi: 10.1016/j.ejphar.2025.177949. Epub 2025 Jul 15.

ABSTRACT

INTRODUCTION: Liver injuries are life-threatening conditions accompanied by endoplasmic reticulum stress (ERS). Hydroxysafflor yellow A (HSYA), an active ingredient in the Chinese herbal medicine safflower, has demonstrated protective effects against acute liver injury. This study aimed to investigate the mechanism by which HSYA alleviates liver damage by regulating ERS through the miR-222-3p-PTEN-Wnt axis.

METHODS: ERS-induced acute liver injury models were established in vitro using tunicamycin-treated BRL-3A cells and in vivo using CCl₄-treated rats. The protective effects of HSYA against ERS-induced acute liver injury were assessed using the Cell Counting Kit-8 assay for cell viability and flow cytometry assay for cell apoptosis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to verify the mRNA and protein expression levels of the ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). To elucidate the regulatory mechanism, the expression of miR-222-3p and Wnt pathway-related markers was measured in both in vitro and in vivo models following HSYA treatment. Additionally, miR-222-3p was transfected into BRL-3A cells to determine the effect of HSYA on ERS and Wnt pathway-related markers and cell apoptosis.

RESULTS: HSYA promoted cell proliferation and decreased cell apoptosis. Compared to tunicamycin, HSYA downregulated GRP78 and CHOP while upregulating PTEN and Axin2 expression. Additionally, it reduced the levels of miR-222-3p, Wnt1, and TCF4 in a dose-dependent manner. However, co-transfection with miR-222-3p diminished these effects.

CONCLUSION: HSYA exerts hepatoprotective effects by modulating ERS via the miR-222-3p-PTEN-Wnt axis.

PMID:40675360 | DOI:10.1016/j.ejphar.2025.177949