IL-1α–IL1R1 Crosstalk Drives Ischaemia-Reperfusion Injury in the Aged Liver: Gut | August 2026

Introduction:

Older livers are particularly vulnerable to hepatic ischaemia-reperfusion injury (HIRI) during liver surgery and transplantation, but the underlying mechanisms remain poorly understood. Using single-cell and spatial transcriptomics across human and animal livers, this study identified a critical inflammatory interaction between senescent liver sinusoidal endothelial cells (LSECs) and hepatocytes that amplifies liver injury with ageing.

Why was this study needed?

Elderly patients increasingly undergo liver resection and transplantation.

Aged livers tolerate ischaemia-reperfusion stress poorly.

The contribution of non-parenchymal cells, particularly LSECs, remains incompletely understood.

Identifying targetable pathways could improve outcomes after liver surgery in older patients.

Results:

Ageing increased senescent LSECs, which released IL-1α through increased MEIS2 activity.

LSEC-derived IL-1α activated IL1R1–NF-κB signalling in hepatocytes, promoting inflammatory liver injury.

Hepatocyte-derived TNF-α further stimulated LSECs, creating a self-amplifying MEIS2–IL-1α–TNF-α inflammatory loop.

Importantly, IL-1α neutralisation significantly reduced liver injury in an aged liver transplantation model.

Clinical Impact:

This study shifts attention from hepatocytes alone toward LSEC–hepatocyte crosstalk as a key driver of age-related surgical liver injury. Targeting the IL-1α–IL1R1 pathway could potentially improve hepatic tolerance to ischaemic stress in elderly patients undergoing liver transplantation or major hepatic resection.

Bottom Line:

Senescent liver endothelial cells amplify ischaemia-reperfusion injury through an IL-1α–IL1R1 inflammatory loop with hepatocytes. Blocking IL-1α reduced injury in preclinical models, identifying a promising therapeutic target for protecting aged livers during surgery and transplantation.