A new study published in Burns & Trauma identifies the c-Jun–Irf8–CD36 axis as a key molecular pathway that drives fibrotic scarring after spinal cord injury (SCI). By targeting this pathway, researchers were able to reduce scar formation, improve vascular remodeling, support axonal regeneration, and promote motor recovery in mouse models.
Fibrotic scarring is one of the major reasons why the injured spinal cord struggles to repair itself. While scar tissue can help stabilize the wound in the early phase, excessive fibrosis later forms a dense barrier that blocks axon regrowth and limits functional recovery. The study, led by researchers from multiple institutions including the Second Affiliated Hospital of Naval Medical University and Shanghai Ninth People's Hospital, used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to map CD36 expression after SCI. They found that CD36 was mainly concentrated in lesion scars and preferentially increased in specific fibroblast subclusters associated with fibrotic progression.
To test whether this pathway could be targeted, the researchers used salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an activator protein-1 (AP-1)/c-Jun inhibitor, in mouse SCI models. SAB reduced P4HB-positive fibroblast accumulation, decreased 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, and Irf8 then promotes CD36 transcription, establishing a c-Jun–Irf8–CD36 signaling cascade.
The authors said the findings suggest a more precise way to think about spinal cord scars. Rather than trying to remove scar tissue completely, they said, 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. They said 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 new stage-adapted strategies for SCI treatment, especially therapies aimed at scar biology during the early post-injury window. 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 shows how single-cell RNA sequencing (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 grants including the National Major Project of Research and Development and the National Natural Science Foundation of China.
