Exosomes Derived from Baicalin-Pretreated Mesenchymal Stem Cells Alleviate Hepatocyte Ferroptosis after Acute Liver Injury via the Keap1-NRF2 Pathway

Acute liver injury (ALI) is characterized as a severe metabolic dysfunction caused by extensive damage to liver cells. Ferroptosis is a type of cell death dependent on iron and oxidative stress, which differs from classical cell death, such as apoptosis and necrosis. Ferroptosis has unique morphological features, which mainly include mitochondrial dissolution and mitochondrial outline reduction. Furthermore, the intracellular accumulation of lipid peroxides directly affects the occurrence of ferroptosis. Baicalin, the main compound isolated from Scutellaria baicalensis, has anti-inflammatory and antioxidative effects. Recently, exosomes derived from preconditioned mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases including ALI. This study investigates the ability of exosomes derived from baicalin-pretreated MSCs (Ba-Exo) to promote liver function recovery in mice with ALI compared with those without pretreatment. Through in vivo and in vitro experiments, this study demonstrates for the first time that Ba-Exo greatly attenuates D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced liver damage and inhibits reactive oxygen species (ROS) production and lipid peroxide-induced ferroptosis. Moreover, P62 was significantly upregulated in Ba-Exo, whereas its downregulation in Ba-Exo counteracted the beneficial effect of Ba-Exo. P62 regulates hepatocyte ferroptosis by activating the Keap1-NRF2 pathway. The beneficial effect of Ba-Exo in inhibiting ferroptosis was also attenuated after the NRF2 pathway was inhibited. Therefore, baicalin pretreatment is an effective and promising approach to optimize the therapeutic efficacy of MSC-derived exosomes in ALI.