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

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

  • Cell Signal. 2026 Feb:138:112246. doi: 10.1016/j.cellsig.2025.112246.
Jun Zhu 1,  Meixia Wang 1,  Yizhi Zhang 2,  Xintao Wang 1,  Lei Dai 3,  Zhu Li 2,  Yangbing Li 1,  Xinxin Zhang 1,  Hongjie Wang 4,  Jie Zhao 5,  Xiaozhou Li 6,  Hong-Hui Wang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemo and Biosensing, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University, Changsha 410082, China.
  • 2 CellWay Bio, Changsha 410082, China.
  • 3 Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China.
  • 4 Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China; Department of Cardiology, Tongji Xianning Hospital, Xianning 437011, Hubei, China.
  • 5 Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine 160 Pujian Road, Pudong New Area, Shanghai 200127, China. Electronic address: [email protected].
  • 6 Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha 410082, Hunan, China.
  • 7 State Key Laboratory of Chemo and Biosensing, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University, Changsha 410082, China. Electronic address: [email protected].
PMID: 41242366 DOI: 10.1016/j.cellsig.2025.112246
Abstract

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.

Keywords

Cytoskeleton; RAI14; Renal fibrosis; Retinoic acid.

Figures
Products