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

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.