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

Background 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. Methods 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. Results 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, TGFβ, 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. Conclusions 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.