Disrupted Alternative Splicing of RAB11FIP3 Contributes to Diabetic Foot Ulcer Dysfunction.

Dysregulation of alternative splicing (AS) has been associated with various complications of diabetes, yet its role in the pathogenesis of diabetic foot ulcers (DFUs) and its involvement in metabolic memory (MM) remain unclear. In this study, we identified specific AS events in RAB11FIP3, notably the full-length (RAB11FIP3-FL) isoform and exon 6 exclusion (RAB11FIP3-Δ6). We found that RAB11FIP3 (FL/Δ6) ratio is significantly elevated in patients with MM and DFUs. Additionally, we demonstrated that knockdown of RAB11FIP3-FL alleviates vascular endothelial damage associated with MM and enhances DFU healing. Furthermore, we identified that HNRNPL promotes the retention of exon 6 in RAB11FIP3-FL, thereby increasing the FL/Δ6 ratio. Mechanistically, our results show that RAB11FIP3-FL promotes the ubiquitination and degradation of HIF-1α through NEDD4L, independent of VHL. In conclusion, our study identifies RAB11FIP3-FL as a pathogenic splicing isoform contributing to impaired DFU healing. Knockdown of RAB11FIP3-FL promotes vascular regeneration and accelerates diabetic wound healing, offering new therapeutic targets for DFU treatment.