New Study Identifies Molecular Pathway Driving Fibrotic Scarring After Spinal Cord Injury, Offering Potential Therapeutic Targets

A new study published in Burns & Trauma identifies the c-Jun–Irf8–CD36 signaling axis as a key molecular driver of fibrotic scarring after spinal cord injury (SCI), a major barrier to neural repair. By combining single-cell RNA sequencing, spatial transcriptomics, drug intervention, and behavioral testing in mouse models, researchers showed that inhibiting CD36 or its upstream regulator c-Jun reduces fibrotic scar formation, improves vascular remodeling, supports axonal regeneration, and promotes motor recovery.

Fibrotic scarring is a critical obstacle in SCI repair. While initial scar formation helps stabilize the injury site and limit inflammation, persistent fibroblast activation leads to excessive extracellular matrix deposition, forming a dense physical and biochemical barrier that blocks axon regrowth. Current clinical strategies, such as decompression surgery and anti-inflammatory treatments, focus on reducing secondary damage rather than directly modulating scar composition.

The research team, from multiple institutions including the Second Affiliated Hospital of Naval Medical University and Shanghai Ninth People's Hospital, used single-cell RNA sequencing and spatial transcriptomic profiling to map CD36 expression after SCI. They found that CD36 is enriched in specific fibroblast subpopulations within the lesion scar, correlating with fibrotic progression. To test therapeutic potential, they used salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an AP-1/c-Jun inhibitor. Both treatments reduced fibroblast accumulation and fibrotic deposition, enhanced angiogenesis, supported axonal regrowth, and improved hindlimb function in mice.

Mechanistically, the study revealed that c-Jun activates Irf8, which in turn promotes CD36 transcription, establishing a c-Jun–Irf8–CD36 cascade. CUT&Tag and dual-luciferase reporter assays confirmed this regulatory connection. Multi-omic analyses showed that T5224 selectively restrained abnormal expansion of CD36-positive fibroblast subclusters and shifted their transcriptional state toward a less fibrotic, more repair-permissive phenotype.

The authors suggest a more precise approach to spinal cord scars: rather than eliminating scar tissue entirely, therapies could tune the scar at the right stage—preserving its early protective role while preventing long-term fibrotic wall formation. Because CD36 and c-Jun are pharmacologically targetable, this work provides a foundation for developing stage-adapted strategies, such as localized drug delivery or combination therapy, to reshape the injury microenvironment. Further validation in larger animal models is needed before translation to human therapy.

The study was supported by multiple grants, including the National Major Project of Research and Development (2022YFA1105500) and the National Natural Science Foundation of China. The original study is available at https://doi.org/10.1093/burnst/tkag020.