LAPTM5 Promotes Age-Related Renal Fibrosis via USP10/PTEN-Mediated Autophagy Inhibition

  • FASEB J. 2026 May 31;40(10):e71905. doi: 10.1096/fj.202504863RR.
Yan Wang  1  2 ,  Qian Gu  1  3 ,  Xueqi Chen  1 ,  Xiaowei Yang  4 ,  Jiajia Zhai  1  5 ,  Meizi Kang  1  6 ,  Jianqing Wu  7 ,  Weihong Zhao  1
Affiliations
  • 1. Division of Nephrology, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2. Geriatrics Department, Nantong First People's Hospital, Southeast University Affiliated Nantong First People's Hospital, Nantong Hospital of Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Nantong, Jiangsu, China.
  • 3. Department of Geriatrics, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
  • 4. Medical School of Nantong University, Nantong, Jiangsu, China.
  • 5. Rehabilitation Medicine Department, Nantong First People's Hospital, Southeast University Affiliated Nantong First People's Hospital, Nantong Hospital of Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Nantong, Jiangsu, China.
  • 6. Nephrology Department, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong Hospital of Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Nantong, Jiangsu, China.
  • 7. Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
PMID: 42149696 DOI: 10.1096/fj.202504863RR
Abstract

Aging accelerates renal fibrosis driven by renal tubular epithelial cells (RTECs) senescence. However, the underlying molecular mechanisms remain elusive. We demonstrate that lysosomal transmembrane protein 5 (LAPTM5) is markedly upregulated in aged kidney models and correlates with renal senescence and fibrosis severity. Mechanistically, LAPTM5 drives RTECs epithelial-mesenchymal transition (EMT) by interacting with USP10 and facilitating its lysosomal degradation, thereby relieving PTEN-mediated inhibition of the PI3K/Akt/mTOR-mediated Autophagy pathway. This accelerates kidney fibrosis. Functionally, PTEN overexpression rescues LAPTM5-induced EMT in RTECs, while the PTEN agonist sophocarpine ameliorates renal fibrosis and preserves function in D-galactose-induced progeroid mice by restoring Autophagy. Our findings identify the LAPTM5-USP10-PTEN axis as a critical regulator of autophagy-mediated renal fibrosis in aging kidney.

Keywords
LAPTM5; PI3K/AKT/mTOR; PTEN; autophagy; fibrosis; kidney; renal tubular epithelial cells; senescence; sophocarpine.
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