The hippo-YAP1/TEAD1-SLC7A5 axis: uncovering a novel therapeutic target for oxalate-induced renal tubular ferroptosis.

Abstract

Objectives: To systematically investigate the regulatory mechanisms of ferroptosis in renal tubular epithelial cells under high oxalate stress, focusing on identifying key upstream signaling pathways and their therapeutic potential.

Methods: We employed HK-2 cell cultures and Glyoxylate-induced mouse models of oxalate nephropathy. Multi-omics approaches including 4D-label-free proteomics, RNA-sequencing, and CUT&Tag were integrated to identify regulatory networks. Functional validation utilized genetic manipulation, pharmacological intervention, chromatin immunoprecipitation, and dual-luciferase reporter assays.

Results: High oxalate dose-dependently induced renal tubular ferroptosis and activated the Hippo pathway, leading to YAP1 phosphorylation and inactivation. Proteomic and multi-omics analyses identified YAP1 as a key regulator and SLC7A5 as its direct transcriptional target via TEAD1. High oxalate disrupted YAP1/TEAD1 binding to the SLC7A5 promoter, downregulating SLC7A5. Functional rescue confirmed that SLC7A5 loss mediated ferroptosis under YAP1 inhibition. Mechanistically, SLC7A5 downregulation restricted leucine availability and suppressed mTOR signaling, while leucine supplementation or mTOR reactivation reversed ferroptosis, demonstrating that SLC7A5 regulates ferroptosis via the leucine/mTOR axis.

Conclusion: We establish the Hippo-YAP1/TEAD1-SLC7A5 axis as a master regulatory pathway controlling oxalate-induced ferroptosis. This pathway represents a promising therapeutic target for oxalate nephropathy and provides fundamental insights into stress-responsive ferroptosis regulation in kidney disease.