Predicting mitophagy-related genes and unveiling liver endothelial cell heterogeneity in hepatic ischemia-reperfusion injury.

Background: Hepatic Ischemia-Reperfusion Injury (HIRI) is a major complication in liver transplants and surgeries, significantly affecting postoperative outcomes. The role of mitophagy, essential for removing dysfunctional mitochondria and maintaining cellular balance, remains unclear in HIRI. Methods: To unravel the role of mitophagy-related genes (MRGs) in HIRI, we assembled a comprehensive dataset comprising 44 HIRI samples alongside 44 normal control samples from the Gene Expression Omnibus (GEO) database for this analysis. Using Random Forests and Support Vector Machines - Recursive Feature Elimination (SVM-RFE), we pinpointed eight pivotal genes and developed a logistic regression model based on these findings. Further, we employed consensus cluster analysis for classifying HIRI patients according to their MRG expression profiles and conducted weighted gene co-expression network analysis (WGCNA) to identify clusters of genes that exhibit high correlation within different modules. Additionally, we conducted single-cell RNA sequencing data analysis to explore insights into the behavior of MRGs within the HIRI. Results: We identified eight key genes (FUNDC1, VDAC1, MFN2, PINK1, CSNK2A2, ULK1, UBC, MAP1LC3B) with distinct expressions between HIRI and controls, confirmed by PCR validation. Our diagnostic model, based on these genes, accurately predicted HIRI outcomes. Analysis revealed a strong positive correlation of these genes with monocytic lineage and a negative correlation with B and T cells. HIRI patients were divided into three subclusters based on MRG profiles, with WGCNA uncovering highly correlated gene modules. Single-cell analysis identified two types of endothelial cells with different MRG scores, indicating their varied roles in HIRI. Conclusions: Our study highlights the critical role of MRGs in HIRI and the heterogeneity of endothelial cells. We identified the macrophage migration inhibitory factor (MIF) and cGAS-STING (GAS) pathways as regulators of mitophagy's impact on HIRI. These findings advance our understanding of mitophagy in HIRI and set the stage for future research and therapeutic developments.

Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells.

Cirrhosis is a progressive and diffuse liver disease characterized by liver tissue fibrosis and impaired liver function. This condition is brought about by several factors, including chronic hepatitis, hepatic steatosis, alcohol abuse, and other immunological injuries. The pathogenesis of liver cirrhosis is a complex process that involves the interaction of various immune cells and cytokines, which work together to create the hepatic homeostasis imbalance in the liver. Some studies have indicated that alterations in the immune microenvironment of liver cirrhosis are closely linked to the development and prognosis of the disease. The noteworthy function of mesenchymal stem cells and their paracrine secretion lies in their ability to promote the production of cytokines, which in turn enhance the self-repairing capabilities of tissues. The objective of this review is to provide a summary of the alterations in liver homeostasis and to discuss intercellular communication within the organ. Recent research on MSCs is yielding a blueprint for cell typing and biomarker immunoregulation. Hopefully, as MSCs researches continue to progress, novel therapeutic approaches will emerge to address cirrhosis.