Spatiotemporal transcriptomic insights into ferroptosis and TFRC-linked immune interactions in ischemia-reperfusion acute kidney injury.

Abstract

Acute kidney injury (AKI) is a common and critical clinical condition with complex pathogenesis and limited early intervention options. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, plays a pivotal role in AKI development. This study aimed to investigate ferroptosis-related gene expression, spatial distribution, and immune interactions in AKI to identify potential therapeutic targets. We analyzed gene expression changes in a mouse model of ischemia-reperfusion-induced AKI and constructed a machine learning-based diagnostic model. This model identified five ferroptosis-related genes (TFRC, TXNRD1, SLC39A14, GCLM, and HMOX1) closely associated with immune cell infiltration. Integration of single-cell and spatial transcriptomics revealed that these genes were predominantly expressed in proximal tubule cells. Notably, TFRC exhibited distinct spatial proximity to infiltrating macrophages. In vivo, administration of the ferroptosis inhibitor NSC306711 significantly reduced macrophage infiltration and renal injury, as confirmed by immunofluorescence. In vitro, co-culture experiments showed that TfR1 degradation alleviated hypoxia-reoxygenation injury in tubular cells and attenuated immune cell activation. This study highlights the central role of ferroptosis in AKI pathogenesis and its interaction with immune components in the renal microenvironment. Targeting ferroptosis, particularly TFRC, may offer a promising strategy to mitigate kidney injury and immune activation in AKI.