PDCD10 ‐ STK24 /25 signaling is a gatekeeper of tubular cell homeostasis and protects against chronic kidney disease

Inherited tubulopathies or injured kidney tubules can initiate inflammatory signaling and drive the progression of chronic kidney disease (CKD) and kidney failure. The early molecular triggers connecting tubular dysfunction to sustained renal inflammation remain poorly defined. Here, we show that deleting Pdcd10, specifically in distal nephron epithelial cells of mice, causes a rapid intrinsic injury response that precipitates chronic renal damage. Pdcd10-deficient kidneys exhibit an immediate and robust upregulation of tubular injury-response genes, followed by inflammatory cell infiltration, and progressive tubulointerstitial damage leading to kidney failure and early mortality. Among the earliest and most strongly induced genes is Lcn2, a known injury marker, whose expression increases significantly in Pdcd10-deficient kidneys. Concurrent deletion of Lcn2 in the same renal epithelial cells further exacerbates renal injury and shortens survival. Pdcd10 deficiency in distal nephrons also upregulates multiple complement pathway genes and promotes accumulation of complement complexes in glomeruli. Finally, in line with PCDC10's known interaction with GCKIII subfamily of sterile-20 like kinases, the combined deletion of Stk24 and Stk25 in distal tubules phenocopies Pdcd10 knockout phenotype, albeit with later onset. Our results demonstrate that PDCD10-STK24/25 signaling is essential for maintaining renal epithelial cell homeostasis. Additionally, our findings reveal that early tubular Lcn2 induction serves as a protective response that helps limit CKD progression following epithelial injury.