MCL1 identified as key regulator of mitochondrial function in liver ischemia-reperfusion injury

Liver Ischemia-Reperfusion Injury (LIRI) is a severe complication following liver transplantation and various surgical procedures, often leading to significant morbidity and mortality. Current therapeutic options are limited, highlighting an urgent need for novel strategies. LIRI is primarily characterized by maladaptive immune responses and profound mitochondrial dysfunction, which drives excessive reactive oxygen species (ROS) generation and cellular damage. Understanding the pivotal regulators linking these two critical pathways is essential for developing effective interventions.

Researchers integrated multiple microarray datasets (GSE12720, GSE112713, GSE23649, GSE151648) and single-cell RNA sequencing (scRNA-seq) data (GSE171539) to identify hub genes in LIRI. They employed weighted gene co-expression network analysis (WGCNA) alongside four machine learning algorithms (SVM, LASSO, RF, and XGBoost) for gene identification. Further single-cell analysis pinpointed cell-specific enrichment. Validation studies confirmed key findings in a murine LIRI model, assessing gene upregulation and macrophage subset presence.

A novel macrophage subset (CSF1R+IL-1B+MCL1+) was identified, characterized by a dual pro-inflammatory and pro-survival phenotype, suggesting enhanced intercellular crosstalk. In silico knockout of MCL1 markedly disrupted immune-related gene networks, particularly those involving NF-κB, apoptosis, and cytokine signaling pathways. Validation studies in a murine LIRI model confirmed both MCL1 upregulation and the presence of this specific macrophage subset.