Single-Cell Transcriptome Reveals the Regulatory Role of STAT3 in Diquat-Induced Oxidative Stress in Piglet Hepatocytes

Le résumé fourni par la source

Oxidative stress (OS) is known to cause severe liver injury in weaning piglets; however, the cellular and molecular mechanisms underlying this process remain poorly understood. In this study, we employed a diquat (DQ)-induced OS model in weanling piglets and performed single-cell transcriptome sequencing of liver tissue to elucidate the key molecular and cellular events involved in OS-induced hepatic damage. First, piglets were treated with 12 mg/kg DQ and the same amount of saline, and the histopathology, biochemical indicators, and single-cell RNA sequencing (scRNA-seq) of piglets were analyzed. Mouse hepatocytes were used to verify the mechanism of differentially expressed genes, including STAT3 knockdown/overexpression, reactive oxygen species (ROS) detection and apoptosis assay. DQ exposure caused significant oxidative damage in the liver of piglets, which was manifested as decreased superoxide dismutase (SOD) activity (p < 0.05), glutathione (GSH) consumption (p < 0.05) and increased malondialdehyde (MDA) (p < 0.05). Cell type-specific responses were revealed by scRNA-seq, with hepatocytes showing the most pronounced transcriptomic alterations (752 genes up-regulated and 918 genes down-regulated). The expression of STAT3 was up-regulated in hepatocytes (p < 0.05) and down-regulated in B cells. The functional enrichment of macrophages involved FOXO/MAPK signaling and OS pathways. In vitro experiments showed that DQ treatment (IC50 = 125.8 μmol/L) led to an increase in ROS content and apoptosis, STAT3 silencing aggravated ROS and apoptosis (p < 0.05), and STAT3 overexpression alleviated ROS and apoptosis (p < 0.05). STAT3 activation increases HO-1 and Bcl-2, while inhibiting Bax and shifting the Bax/Bcl-2 ratio toward cell survival. It has been shown that DQ induces OS and apoptosis in a cell type-dependent manner, in which STAT3 plays a key regulatory role in antioxidant defense and cell survival. Targeting STAT3 may be a therapeutic strategy for DQ-induced hepatotoxicity.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.