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Research Article: Ferroptosis-associated myeloid cell heterogeneity and inflammatory amplification following spinal cord injury

Date Published: 2026-04-22

Abstract:
Spinal cord injury (SCI) causes severe and persistent neurological dysfunction. Ferroptosis has been implicated in multiple neurological disorders, but its contribution to SCI and its relationship to myeloid-cell responses, inflammatory amplification and disturbed iron homeostasis remain unclear. We integrated public bulk RNA-sequencing and single-cell RNA-sequencing datasets with experiments in a rat SCI model to define ferroptosis-associated changes across the molecular, cellular and tissue levels. Differential expression, pathway enrichment, co-expression and protein–protein interaction analyses, pseudotime inference and cell–cell communication modelling were used to identify candidate molecules and relevant myeloid subpopulations, followed by qPCR, western blotting and immunofluorescence validation. Ferroptosis-associated molecular alterations in SCI showed marked temporal dynamics and remained embedded within pathological networks linked to inflammation, oxidative stress and hypoxic responses. Single-cell analysis indicated that these signals were concentrated primarily in myeloid cells, particularly the HMOX1-high M1a and M1b subclusters. Pseudotime and cell–cell communication analyses further suggested that these subpopulations progress along a continuous trajectory towards inflammation-amplifying states and may influence the local microenvironment through MIF, TGF?, PTN and CD99 signalling. Animal experiments further showed that sustained inflammatory activation occurs in parallel with dysregulation of ferroptosis-associated molecules, accompanied by local myeloid-cell activation and enhanced HMOX1-associated stress responses. In SCI, ferroptosis-associated signals appear to be concentrated within HMOX1-associated myeloid subpopulations and may be sustained through cell-state reprogramming and intercellular signaling networks. HMOX1 emerges as a candidate hub linking disturbed iron handling, ferroptosis and myeloid inflammatory remodeling.

Introduction:
Spinal cord injury (SCI) causes severe and persistent neurological dysfunction. Ferroptosis has been implicated in multiple neurological disorders, but its contribution to SCI and its relationship to myeloid-cell responses, inflammatory amplification and disturbed iron homeostasis remain unclear.

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