Baicalein facilitates hepatic stellate cell ferroptosis via the DNMT1/SCARA5/GPX4 axis

Activated hepatic stellate cells (HSCs), the main collagen producers during liver fibrosis, can be controlled by ferroptosis. Baicalein, a traditional medicinal compound obtained from Scutellaria baicalensis roots, exhibits anti-inflammatory, antifibrotic, and hepatoprotective properties. Recently, both SCARA5 and DNMT1 have been reported to be involved in regulating ferroptosis in various cancers.

Whether baicalein can inhibit HSC activation through ferroptosis remains unclear.

Masson staining, western blotting, and polymerase chain reaction (PCR) were used to assess the effects of baicalein on HSC activation. Ferroptosis indicators were detected. In addition, co-immunoprecipitation (Co-IP) and molecular docking were used to examine the correlation between SCARA5 and GPX4.

Baicalein inhibited HSC activation and alleviated liver fibrosis. It reduced GPX4 expression to induce HSC ferroptosis, as evidenced by an increase in ferrous ion (Fe²⁺), malondialdehyde (MDA), and reactive oxygen species (ROS) levels and a decrease in glutathione (GSH) levels. In addition, baicalein significantly promoted SCARA5 expression. Co-IP and molecular docking collectively validated the negative effects of SCARA5 on GPX4 expression. The SCARA5 promoter harbored a CpG island, and its methylation was facilitated by DNMT1, which could be targeted by baicalein. Knockdown of SCARA5 inhibited baicalein-induced ferroptosis and inactivation of HSCs, whereas HSC-specific knock-in of SCARA5 alleviated liver fibrosis in mice.

Baicalein promotes HSC ferroptosis and inactivation by targeting the DNMT1/SCARA5/GPX4 axis, thereby alleviating liver fibrosis.