Targeting the Jun-Irf8-CD36 axis attenuates fibrotic scar formation and promotes functional recovery after spinal cord injury

Fibrotic scar formation constitutes a significant pathological obstacle that impedes neural regeneration and long-term functional recovery following spinal cord injury (SCI). However, the spatial distribution of key pro-fibrotic mediators within lesion scars and the upstream regulatory mechanisms driving fibroblast activation remain inadequately defined. This study aims to characterize CD36-associated fibrotic remodeling after SCI and to determine whether targeting the c-Jun–Irf8–CD36 axis could attenuate scar formation, improve the regenerative microenvironment, and promote functional recovery.

This study integrated single-cell ribonucleic acid sequencing and spatial transcriptomic profiling to characterize CD36 expression patterns and identify fibroblast subpopulations within SCI scars. Pharmacological interventions were administered in mouse SCI models, using salvianolic acid B (SAB) to inhibit CD36 and T5224 to block AP-1/c-Jun activity. Histological and immunofluorescence analyses were performed to assess fibroblast accumulation, extracellular matrix deposition, angiogenesis, and axonal regeneration, alongside longitudinal behavioral evaluations of locomotor function. Mechanistic validation of the regulatory pathway was achieved through CUT&Tag and dual-luciferase reporter assays to investigate c-Jun–Irf8–CD36 transcriptional regulation, complemented by integrated single-cell/spatial analyses to assess fibroblast subcluster remodeling post-treatment.

Spatial and single-cell analyses demonstrated that CD36 is predominantly localized within lesion scars, correlating with fibrotic progression and preferentially upregulated in specific fibroblast subclusters. SAB-mediated CD36 inhibition markedly reduced P4HB⁺ fibroblast accumulation, alleviated fibrotic deposition, enhanced angiogenesis and axonal regeneration, and improved hindlimb functional recovery. Mechanistically, c-Jun was upregulated in scar regions and indirectly promoted CD36 transcription through Irf8 activation, establishing a c-Jun–Irf8–CD36 signaling axis. CUT&Tag and reporter assays confirmed c-Jun binding to the Irf8 promoter, leading to Irf8-driven CD36 transcription. Similarly, T5224 downregulated CD36 expression, reduced fibroblast aggregation and matrix deposition, facilitated vascular remodeling, and promoted early functional recovery. These findings demonstrate that modulating this signaling pathway can significantly inhibit pathological scar formation and facilitate approximately scar-free healing, thereby providing an ideal microenvironment for tissue regeneration. Multi-omic analyses further revealed that T5224 selectively inhibited the aberrant expansion of CD36⁺ fibroblast subclusters and reprogrammed their transcriptional states toward a less fibrotic phenotype.

The c-Jun–Irf8–CD36 axis serves as a pivotal regulator of fibrotic scar formation after SCI. Targeting this pathway through CD36 inhibition (SAB) or AP-1/c-Jun blockade (T5224) attenuates fibrosis, remodels the scar microenvironment, enhances tissue repair, and promotes functional recovery, highlighting a promising therapeutic strategy for central nervous system injury.