Fibrotic scarring is a major obstacle to spinal cord repair, but a new study published in Burns & Trauma identifies a molecular pathway that could be targeted to reduce scarring and promote recovery. The research, conducted by a team from multiple Chinese institutions, reveals that the c-Jun–Irf8–CD36 signaling axis drives the accumulation of fibrosis-forming fibroblasts after spinal cord injury (SCI). By inhibiting CD36 or its upstream regulator c-Jun, the researchers were able to reduce scar formation, improve blood vessel remodeling, support nerve regeneration, and enhance motor function in mouse models.
Spinal cord injury often leads to permanent motor and sensory deficits because the damaged tissue does not heal like other tissues. In the acute phase, scar formation helps stabilize the wound and limit inflammation, but persistent fibroblast activation leads to excessive extracellular matrix deposition that creates a dense barrier blocking axon regrowth. Current treatments focus on reducing secondary damage rather than modifying the scar itself. The study aimed to uncover the molecular mechanisms controlling pathological scar formation to develop more targeted therapies.
Using single-cell RNA sequencing and spatial transcriptomics, the researchers mapped CD36 expression after SCI and found it concentrated in lesion scars, particularly in fibroblast subpopulations linked to fibrotic progression. They tested two inhibitors in mouse SCI models: salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an AP-1/c-Jun inhibitor. Both treatments reduced fibrotic scarring. SAB decreased P4HB-positive fibroblast accumulation, reduced fibrotic deposition, enhanced CD31-marked angiogenesis, supported axonal regrowth, and improved hindlimb functional recovery. T5224 also lowered CD36 expression, reduced fibroblast aggregation and ECM deposition, promoted vascular remodeling, and improved early motor recovery.
Mechanistically, the study showed that c-Jun activates Irf8, which then promotes CD36 transcription, establishing a c-Jun–Irf8–CD36 signaling cascade. CUT&Tag and dual-luciferase reporter assays confirmed this regulatory connection. Multi-omic analyses revealed 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 findings suggest a more precise approach to managing spinal cord scars: rather than removing scar tissue entirely, the goal may be to modulate the scar at the right stage—preserving its early protective role while preventing fibroblasts from building a long-lasting fibrotic wall. The identification of 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.
Because both CD36 and c-Jun are pharmacologically targetable, the work provides a foundation for testing localized drug delivery, combination therapy, or precision approaches that act on pathogenic fibroblast subtypes while preserving tissue stability. The study also demonstrates how single-cell RNA sequencing and spatial transcriptomics can reveal not only which cells are present in 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 SCI therapy.
The study was published in Burns & Trauma with the DOI 10.1093/burnst/tkag020.
