IL1B-high macrophages promote ferroptosis-like lipid peroxidation injury in Crohn's disease intestinal epithelium
4 affiliations
- 1Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- 2Department of Anorectal Surgery, The First People's Hospital of Chenzhou, Chenzhou, Hunan, 423000, China
- 3Fourth Department of Internal Medicine, Chenggong District People's Hospital of Kunming, Kunming, Yunnan, 650500, China
- 4Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China; Corresponding author. Department of General Surgery, The Second Xiangya Hospital of Central South University, 410011 Changsha, China.
Abstract
Crohn's disease (CD)-associated mucosal injury involves immune-cell infiltration, epithelial cell death, and junctional disruption, but how specific myeloid states contribute to epithelial lipid peroxidation remains unclear. We integrated longitudinal single-cell transcriptomics, spatial transcriptomics, macrophage–epithelial co-culture, epithelial RNA-seq, exploratory candidate-gene prioritization, GPX4 functional validation, and a TNBS-induced chronic colitis model to investigate IL1B-high macrophage-associated epithelial injury. In paired pretreatment and post-treatment biopsies, persistent active disease (POST-ACT) showed a higher relative representation of myeloid cells, increased epithelial programmed-cell-death-related transcriptional activity, and stronger predicted myeloid–epithelial communication than remission samples. Myeloid subclustering identified a pro-inflammatory IL1B-high macrophage state relatively enriched in pooled POST-ACT cells, while RCTD-based spatial mapping supported non-random local co-occurrence of inferred IL1B-high macrophage and injury-associated epithelial signals. In vitro, IL1B-high macrophage co-culture increased epithelial cell death, reduced GSH, and increased MDA and lipid ROS in FHC and NCM460 cells; these changes were partially attenuated by Ferrostatin-1. Integration of ferroptosis-related genes, differential expression, LASSO, and random forest prioritized GPX4, PGD, and LPCAT3. GPX4 was consistently downregulated and was selected for functional validation; GPX4 overexpression partially restored ZO-1, E-cadherin, and Occludin expression. Blocking IL-1β/IL1R1 signaling with an anti-IL-1β neutralizing antibody or the IL1R1 antagonist AF12198 attenuated lipid peroxidation, GPX4 downregulation, and loss of junction-associated molecules in the shared co-culture system. In TNBS colitis, Ferrostatin-1 or anti-IL-1β treatment alleviated selected mucosal injury phenotypes, and adding IL-1β blockade to anti-TNF produced incremental improvement over anti-TNF alone. Collectively, these findings support an IL1B-high macrophage-associated epithelial injury axis involving IL-1β–IL1R1 signaling, reduced GPX4-related lipid-peroxide defense, ferroptosis-like lipid peroxidation injury, and junction-associated molecular alterations in CD.
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BibTeX
@article{sun2026il1bhigh,
title = {{IL1B-high macrophages promote ferroptosis-like lipid peroxidation injury in Crohn's disease intestinal epithelium}},
author = {Qi Sun and Zhixian Jiang and Xueliang Chen and Ganglei Liu and Mengyao Song and Lianwen Yuan and Lichao Yang},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104403},
url = {https://doi.org/10.1016/j.redox.2026.104403},
note = {CC BY},
}
RIS
TY - JOUR
TI - IL1B-high macrophages promote ferroptosis-like lipid peroxidation injury in Crohn's disease intestinal epithelium
AU - Qi Sun
AU - Zhixian Jiang
AU - Xueliang Chen
AU - Ganglei Liu
AU - Mengyao Song
AU - Lianwen Yuan
AU - Lichao Yang
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104403
UR - https://doi.org/10.1016/j.redox.2026.104403
AB - Crohn's disease (CD)-associated mucosal injury involves immune-cell infiltration, epithelial cell death, and junctional disruption, but how specific myeloid states contribute to epithelial lipid peroxidation remains unclear. We integrated longitudinal single-cell transcriptomics, spatial transcriptomics, macrophage–epithelial co-culture, epithelial RNA-seq, exploratory candidate-gene prioritization, GPX4 functional validation, and a TNBS-induced chronic colitis model to investigate IL1B-high macrophage-associated epithelial injury. In paired pretreatment and post-treatment biopsies, persistent active disease (POST-ACT) showed a higher relative representation of myeloid cells, increased epithelial programmed-cell-death-related transcriptional activity, and stronger predicted myeloid–epithelial communication than remission samples. Myeloid subclustering identified a pro-inflammatory IL1B-high macrophage state relatively enriched in pooled POST-ACT cells, while RCTD-based spatial mapping supported non-random local co-occurrence of inferred IL1B-high macrophage and injury-associated epithelial signals. In vitro, IL1B-high macrophage co-culture increased epithelial cell death, reduced GSH, and increased MDA and lipid ROS in FHC and NCM460 cells; these changes were partially attenuated by Ferrostatin-1. Integration of ferroptosis-related genes, differential expression, LASSO, and random forest prioritized GPX4, PGD, and LPCAT3. GPX4 was consistently downregulated and was selected for functional validation; GPX4 overexpression partially restored ZO-1, E-cadherin, and Occludin expression. Blocking IL-1β/IL1R1 signaling with an anti-IL-1β neutralizing antibody or the IL1R1 antagonist AF12198 attenuated lipid peroxidation, GPX4 downregulation, and loss of junction-associated molecules in the shared co-culture system. In TNBS colitis, Ferrostatin-1 or anti-IL-1β treatment alleviated selected mucosal injury phenotypes, and adding IL-1β blockade to anti-TNF produced incremental improvement over anti-TNF alone. Collectively, these findings support an IL1B-high macrophage-associated epithelial injury axis involving IL-1β–IL1R1 signaling, reduced GPX4-related lipid-peroxide defense, ferroptosis-like lipid peroxidation injury, and junction-associated molecular alterations in CD.
SN - 2213-2317
ER -