A new study published in Burns & Trauma identifies the c-Jun–Irf8–CD36 signaling axis as a key driver of fibrotic scarring after spinal cord injury (SCI), and shows that pharmacological inhibition of CD36 or its upstream regulator c-Jun can reduce scar formation, promote tissue repair, and improve functional recovery in mouse models. The findings, reported by researchers from multiple Chinese institutions, offer a molecular roadmap for developing stage-adapted therapies that modulate—rather than eliminate—scar tissue to support regeneration.
Fibrotic scarring is a major obstacle to spinal cord repair. While early scar formation helps stabilize the injury site and limit inflammation, persistent fibroblast activation leads to excessive extracellular matrix deposition that forms a dense, inhibitory barrier. This blocks axon regrowth and impairs functional recovery. Current treatments, such as decompression surgery and anti-inflammatory drugs, address secondary damage but do not target the scar itself.
To explore the molecular mechanisms behind pathological scarring, the research team used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to profile gene expression in mouse spinal cords after injury. They found that CD36, a protein involved in fatty acid uptake and signaling, was highly expressed in specific fibroblast subpopulations within lesion scars. These CD36-enriched fibroblasts accumulated over time and correlated with fibrotic progression.
The researchers then tested two inhibitors: salvianolic acid B (SAB), which blocks CD36, and T5224, which inhibits activator protein-1 (AP-1)/c-Jun. In mouse SCI models, both treatments reduced fibrotic scarring. SAB decreased the accumulation of P4HB-positive fibroblasts, reduced fibrotic deposition, enhanced CD31-positive blood vessel formation, supported axonal regrowth, and improved hindlimb motor function. T5224 similarly lowered CD36 expression, reduced fibroblast aggregation and extracellular matrix deposition, promoted vascular remodeling, and improved early motor recovery.
Mechanistically, the study showed that c-Jun activates the transcription factor Irf8, which in turn drives CD36 expression, establishing the c-Jun–Irf8–CD36 cascade. CUT&Tag and dual-luciferase reporter assays confirmed the regulatory connection. Multi-omic analyses revealed that T5224 selectively restrained the expansion of CD36-positive fibroblast subclusters and shifted their transcriptional state toward a less fibrotic, more repair-permissive phenotype.
“Rather than trying to remove scar tissue completely, 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,” the authors noted. 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.
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 scRNA-seq 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 (DOI: 10.1093/burnst/tkag020) and supported by several Chinese funding agencies.
