A new study published in Burns & Trauma has identified a molecular pathway that drives fibrotic scarring after spinal cord injury (SCI), offering potential targets for therapies that could improve recovery. The research, conducted by a team from multiple institutions including the Second Affiliated Hospital of Naval Medical University and Shanghai Jiao Tong University School of Medicine, highlights the c-Jun–Irf8–CD36 signaling cascade as central to the formation of dense scar tissue that blocks nerve regeneration.
Fibrotic scarring is a major obstacle to spinal cord repair. While initial scar formation helps stabilize the injury, excessive fibrosis later creates a physical and biochemical barrier that prevents axon regrowth and limits functional recovery. Current treatments, such as decompression surgery and anti-inflammatory drugs, primarily address secondary damage rather than the scar itself. The study aimed to uncover the molecular mechanisms behind pathological scar formation to enable more targeted interventions.
Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on mouse models, the researchers mapped CD36 expression after SCI. They found that CD36 was concentrated in lesion scars, particularly in specific fibroblast subclusters associated with fibrotic progression. To test therapeutic potential, they administered salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an activator protein-1 (AP-1)/c-Jun inhibitor, to injured mice. Both treatments reduced fibrotic scarring: SAB decreased P4HB-positive fibroblast accumulation and fibrotic deposition, while enhancing angiogenesis and axonal regrowth, leading to improved hindlimb function. T5224 similarly lowered CD36 expression, reduced fibroblast aggregation and extracellular matrix deposition, promoted vascular remodeling, and improved early motor recovery.
Mechanistically, the study established that c-Jun activates Irf8, which then promotes CD36 transcription, forming the c-Jun–Irf8–CD36 signaling cascade. CUT&Tag and dual-luciferase reporter assays confirmed this regulatory connection. Multi-omic analyses showed that T5224 selectively restrained the abnormal expansion of CD36-positive fibroblast subclusters and shifted their transcriptional state toward a less fibrotic, more repair-permissive phenotype.
The authors suggest that rather than removing scar tissue entirely, the goal should be to modulate it at the right stage—preserving its early protective role while preventing the formation of a long-lasting fibrotic wall. Identifying c-Jun, Irf8, and CD36 as connected control points provides a clearer route for developing therapies that reshape the injury microenvironment and give regenerating axons a better chance to reconnect.
These findings may support stage-adapted strategies for SCI treatment, particularly therapies targeting scar biology during the early post-injury window. Because both CD36 and c-Jun are pharmacologically targetable, the work lays a foundation for localized drug delivery, combination therapy, or precision approaches that act on pathogenic fibroblast subtypes while preserving tissue stability. The study also demonstrates how scRNA-seq and spatial transcriptomics can reveal not only which cells are present at an injury site but where they act and how they change after treatment. Further validation in larger animal models and preclinical systems will be needed before translation to human therapy.
The study was supported by the National Major Project of Research and Development, the China Postdoctoral Science Foundation, the Shanghai Pujiang Program, the National Natural Science Foundation of China, and other funding sources. The full article is available in Burns & Trauma at https://doi.org/10.1093/burnst/tkag020.
