Renal tubular-derived retinoic acid drives renal fibrosis via a RAI14-TRIOBP-YAP mechanotransduction axis.

Retinoic acid (RA), a metabolite of vitamin A, exerts paradoxical effects in tissue repair, promoting regeneration in some contexts while driving fibrosis in others. However, the mechanisms governing this functional switch remain elusive. Here, we identify RA as a key paracrine signal that links tubular epithelial injury to fibroblast activation in renal fibrosis. Spatial metabolomics and single-cell transcriptomics reveal that ALDH1A2-mediated RA synthesis is upregulated in injured renal tubules, while RA receptor signaling is enriched in interstitial fibroblasts. RA stimulation induces fibroblast-to-myofibroblast transition (FMT) by upregulating RAI14, a cytoskeletal adaptor that binds and stabilizes TRIOBP, thereby preventing its HECTD1-mediated ubiquitination and degradation. This stabilization enhances F-actin assembly and cytoskeletal tension, leading to YAP nuclear translocation and activation of profibrotic transcriptional programs. Genetic ablation of RAI14 significantly attenuates renal fibrosis in vivo. Together, our findings uncover a tubule-derived RA-RAI14-TRIOBP-YAP axis that translates epithelial injury into fibroblast mechanotransduction, providing mechanistic insight into epithelial-mesenchymal communication and a potential therapeutic target for fibrotic kidney disease.