Work

Pi4ka downregulation triggers Creb3l2-dependent lysosomal dysfunction to promote maladaptive tubular remodeling and immune activation in acute kidney injury

Year: 2026

Type: article

Abstract: Acute kidney injury (AKI) is driven by maladaptive tubular responses, yet upstream regulators remain incompletely understood. Here, we identify phosphatidylinositol 4-kinase alpha ( Pi4ka ) as a critical determinant of proximal tubule cell (PTC) homeostasis and injury progression. PI4KA expression was reduced in human diseased kidneys and negatively correlated with renal function. Single-cell RNA sequencing in mouse models revealed that Pi4ka deficiency preferentially perturbs specific PTC states, including Slc34a1 + Ccn1 + , and Slc34a1 + Apob + populations, which diverge along distinct maladaptive trajectories. From these trajectories we derived a 40-gene injury signature enriched for lysosome-associated pathways, and functional assays showed that lysosomal dysfunction is an early event linking Pi4ka loss to ER stress, impaired autophagy, and proteostasis disruption. Transcriptional network analysis identified Creb3l2 as a central regulator of lysosomal activation. Notably, Creb3l2 perturbation suppressed stress and cell-death programs while promoting transcriptional programs associated with repair and phospholipid metabolism. Ligand–receptor inference further indicated that Pi4ka -deficient PTCs shape a pro-inflammatory immune microenvironment via immunomodulatory gene activation, an effect abolished by Creb3l2 deletion. Collectively, these findings define a Pi4ka –lysosome– Creb3l2 axis that coordinates tubular injury, maladaptive remodeling, and immune activation, highlighting potential therapeutic targets to limit AKI progression.

Source: Cell Death and Disease

DOI: 10.1038/s41419-026-08794-y