A new study published in Burns & Trauma identifies a molecular pathway that drives excessive fibrotic scarring after spinal cord injury (SCI), offering potential therapeutic targets to improve repair. The research, led by teams from multiple Chinese institutions, reveals that the c-Jun–Irf8–CD36 signaling cascade promotes the accumulation of CD36-enriched fibroblasts that form a dense barrier blocking axon regrowth.
Fibrotic scarring is a major obstacle to spinal cord repair. While early scar formation helps stabilize the wound, persistent fibroblast activation leads to excessive extracellular matrix deposition that physically and biochemically hinders regeneration. Current treatments focus on reducing secondary damage rather than modulating the scar itself. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the researchers mapped CD36 expression after SCI, finding it concentrated in lesion scars and specifically increased in fibroblast subclusters associated with fibrotic progression.
To test therapeutic potential, the team used salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an AP-1/c-Jun inhibitor, in mouse SCI models. SAB reduced fibroblast accumulation, decreased fibrotic deposition, enhanced angiogenesis (marked by CD31), supported axonal regrowth, and improved hindlimb functional recovery. T5224 similarly 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 the c-Jun–Irf8–CD36 cascade. CUT&Tag and dual-luciferase reporter assays confirmed this regulatory connection.
Multi-omic analyses further demonstrated 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 may be to tune the scar at the right stage—preserving its early protective role while preventing fibroblasts from building 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.
Because both CD36 and c-Jun are pharmacologically targetable, this 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 highlights how scRNA-seq and spatial transcriptomics can reveal not only which cells are present 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 full study, titled "CD36-enriched fibroblast subpopulations accumulate in lesion scars and can be therapeutically modulated to improve the repair environment," is available in Burns & Trauma. For more information about the research, visit Chuanlink Innovations.
