Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation

The gap

Evidence profile

Sourced from the inline gaps and future work and abstract of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 27 times in total.

Supporting evidence — 3 representative gaps

• The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity (2025) · Antioxidants · cited 27× · doi

  However, further research is necessary in order to understand the role of the eIF2α-ATF4 signaling pathway across vari- ous models of liver damage and to determine the long-term safety of eIF2α-ATF4-targeted therapies in clinical settings. Further research is required in order to explore how the ER-stress-induced eIF2α-ATF4 signaling pathway interacts with ferroptotic signaling pathways and to identify potential therapeutic targets for diseases characterized by these complex cellular dynamics. Furthermore, it is plausible that PERK-eIF2α-ATF4 activation could influence iron-mediated ferroptosis; however, this was not explored in the current study.

  generalinline gaps
  Keywords: signaling further order pathway necessary understand role across vari models liver damage determine long term
• Targeting ferroptosis and mitochondrial ROS: organoprotective mechanisms of anesthetic conditioning in liver transplantation (2026) · Frontiers in Molecular Biosciences · doi

  mechanistic incorporate immunosuppressant exposure as a variable in experimental models of hepatic IRI and, where possible, correlate drug levels and mitochondrial function biomarkers with ferroptosis-specific endpoints in transplant recipient cohorts. should Integrated mechanistic model, biomarkers, and therapeutic translation The combination of the impact of ferroptosis and microvascular injury along with the increased levels of ROS, the presence of systemic inflammation, the degree of endothelial dysfunction, and subsequent microvascular failure provide a better basis to explain liver graft injury than a singular pathogenic injury. Ischemia- reperfusion injury of the liver cannot be solely attributed to either oxidative stress or to inflammation (Choi and Lim, 2023). Upon reperfusion, a self sustaining cascade occurs where the impairment of mitochondrial structure leads to an increase in ROS, leading to lipid peroxidation through the action of ROS, and lipid peroxidation leads to ferroptotic injury of cellular membranes. Once cellular injury has occurred, the dying cells release damage associated molecular patterns (DAMPs) which trigger the activation of Kupffer cells, neutrophils, complement systems, and endothelial responses (Mihm, 2018). As a result of the inflammatory response produced by these events, there will be additional worsening of sinusoidal stasis, tissue hypoxia, and secondary mitochondrial injury (Nastos et al., 2014). Thus, this is a cyclical event rather than a linear sequence of events. The model described above can also explain why many single target therapeutic strategies have failed to achieve significant clinical results. Total elimination of ROS may not be sufficient to prevent injury when other mechanisms of injury (iron dependent lipid peroxidation, endothelial edema, and enhanced inflammatory stimulation) continue to operate. Similarly, while reducing lipid injury from ferroptosis may be beneficial for reducing lipid injury, restoration of mitochondrial ATP production and improvement in microvascular perfusion will not occur. Consequently, protective interventions in the clinic would likely need to employ multi-site intervention in order to modulate the stability of mitochondria, remove lipid radicals and toxic metabolites from the system, minimize excessive inflammatory responses, and restore sinusoidal flow. While mitochondrial ROS plays an important role in this network due to its ability to cause injury to mitochondrial components upon reoxygenation, it should not be viewed as the sole source of injury. Mitochondrial injury caused by ischemia involves multiple factors including energy depletion, calcium overload, decre

  generalfuture work
  Keywords: injury mitochondrial lipid ferroptosis microvascular endothelial peroxidation inflammatory mechanistic levels biomarkers model therapeutic inflammation explain
• Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress (2026) · JCI Insight · doi

  Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation, induces sterile inflammation that reshapes tissue immunity and contributes to organ dysfunction, yet the intercellular circuits that spatially orchestrate these responses within the hepatic immune microenvironment remain incompletely defined.

  generalabstractevidence 5/5
  Keywords: immune surgical stress liver ischemia reperfusion injury characterized robust neutrophil infiltration activation induces sterile inflammation

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