Integrative single-cell and spatial transcriptomic analyses identify LMX1B as a tumor suppressor orchestrating the GDF15–ATP4B axis in renal cell carcinoma

Abstract

Highlights • Integrative single-cell and spatial transcriptomic analyses identify LMX1B as a previously unrecognized tumor suppressor in renal cell carcinoma.• LMX1B-associated epithelial cells function as central signaling hubs within the tumor microenvironment, engaging in spatially organized bidirectional communication with stromal and immune compartments.• LMX1B transcriptionally activates GDF15 through direct promoter binding, establishing the LMX1B–GDF15–ATP4B axis as a critical tumor-suppressive regulatory cascade.• GDF15 induces mitochondrial apoptosis via ROS-mediated membrane potential depolarization and Bax/Bcl-2-caspase-3 cascade activation in RCC cells.• These findings identify LMX1B as a promising prognostic biomarker and provide multiple druggable nodes for precision therapeutic intervention in renal malignancy.