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

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.