Iron overload exaggerates renal ischemia-reperfusion injury by promoting tubular cuproptosis via interrupting function of LIAS.

Renal ischemia-reperfusion injury (RIRI), a major contributor to acute kidney injury (AKI) and delayed graft function (DGF), is closely associated with dysregulation of metal ion homeostasis. Although copper and iron metabolism exhibit interconnected regulatory pathways, the temporal dynamics and functional interplay of these metal ions in RIRI pathogenesis remain poorly understood. Our study demonstrates that cuproptosis and ferroptosis, two distinct forms of cell death induced by metal ion overload, occur simultaneously within 6 h after reperfusion. Notably, ischemia-reperfusion injury induced iron overload significantly sensitizes renal tubular cells to copper-mediated cytotoxicity. Mechanistic investigations demonstrate that hypoxia-reoxygenation triggers Fe (II) accumulation, which subsequently downregulates [4Fe-4S] cluster assembly proteins. This impairment directly compromises the structural integrity of the cuproptosis-regulating protein LIAS by inducing [4Fe-4S] cluster loss, ultimately leading to defective protein lipoylation that drives cuproptosis progression. Crucially, these pathological effects can be attenuated through either overexpression of [4Fe-4S] cluster assembly machinery or therapeutic application of iron-chelating agents. Our findings establish a novel iron-copper crosstalk mechanism in RIRI pathophysiology and propose targeted strategies focusing on [4Fe-4S] cluster homeostasis and iron chelation for clinical intervention.