The THBS1-CD47 axis drives macrophage-hepatocyte crosstalk to exacerbate apoptosis by inhibiting PI3K-AKT-NF-κB signaling in hepatic ischemia-reperfusion injury.
Bulk transcriptomic analysis identified 25 differentially expressed programmed cell death-related genes (DE-PCDRGs) consistently upregulated in HIRI samples.
Machine learning algorithms identified 5 hub DE-PCDRGs (THBS1, MAP1LC3B, PPP1R15A, CXCL8, ZC3H12A) closely related to HIRI.
High-risk HIRI patients showed pronounced enrichment of 5 specific programmed cell death patterns: anoikis, immunogenic cell death, NETosis, netotic cell death, and pyroptosis.
Single-cell transcriptomic analysis uncovered 19 diverse PCD patterns in HIRI samples and identified 12 distinct PCD patterns within the HIRI sample microenvironment.
The HIRI animal model confirmed occurrence of apoptosis in liver tissue and upregulation of THBS1 specifically in macrophages.
Macrophage-derived THBS1 directly engaged hepatocyte CD47, suppressing the PI3K-AKT-NF-κB signaling pathway and promoting apoptosis.
The study identified heterogeneous programmed cell death patterns as a key pathological process in HIRI, with THBS1-CD47 nominated as a promising therapeutic candidate target.
This research suggests that liver damage caused by ischemia-reperfusion injury (when blood flow is cut off and then restored, as happens during liver transplantation) involves a complex interplay between different types of programmed cell death. By analyzing gene expression data from multiple patient datasets and using machine learning, the researchers identified 5 key genes that can predict how severely a patient will be affected, and found that high-risk patients show activation of specific cell death programs including pyroptosis and NETosis. The study also found that immune cells called macrophages play a central role in worsening the injury by releasing a protein called THBS1 that binds to a receptor (CD47) on liver cells, triggering a chain of molecular signals that ultimately causes liver cell death. The researchers confirmed these findings both in animal models and in laboratory cell culture experiments. When macrophages and liver cells were grown together, the THBS1 from macrophages binding to CD47 on liver cells switched off a protective signaling pathway (PI3K-AKT-NF-κB), making the liver cells more likely to undergo apoptosis (a form of programmed cell death). This communication between macrophages and liver cells therefore amplifies the damage during ischemia-reperfusion injury. This research suggests that the THBS1-CD47 interaction could be a target for new treatments to reduce liver damage in transplant patients. By blocking this communication pathway between macrophages and liver cells, it may be possible to preserve more liver tissue during and after transplantation, potentially improving patient outcomes. The study also provides a gene-based risk prediction model that could help identify patients at higher risk of severe injury.
Xie M, Zhang C, Zhu L, Pei Y, Liang C, Fu L, et al.. (2026). Integrated transcriptomic profiling of programmed cell death patterns unveils macrophage-hepatocyte crosstalk via THBS1-CD47 axis in hepatic ischemia-reperfusion injury.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1769849