Lead binds HIF-1α contributing to depression-like behaviour through modulating mitochondria-associated astrocyte ferroptosis.

Environmental lead (Pb) exposure has been implicated in the development of depression. Here we show that Pb induces depression-like behaviour in mice by triggering ferroptosis. Single-cell RNA sequencing revealed that astrocytes exhibited the highest ferroptosis scores in brain tissue following Pb exposure. Further analysis identified HIF-1α as an early regulator of ferroptosis-related genes in astrocytes. Computational model and experimental validation demonstrated that Pb²⁺ binds to the proline hydroxylation site of HIF-1α at position 138, stabilizing the protein structure and facilitating its nuclear translocation. Subsequently, the ferroptosis-related DEGs of the transcriptional regulatory network of HIF-1α in astrocyte ferroptosis were mainly enriched in mitochondrial dysfunction, wherein the role of voltage-dependent anion channel 1 (VDAC1) is notable. Further experiments also confirmed that HIF-1α promotes VDAC1 transcription, regulating mitochondrial dysfunction in astrocytes following Pb exposure. These findings indicate that astrocyte ferroptosis contributes to depression-like behaviour following Pb exposure through the HIF-1α/VDAC1 axis. Pb appears to stabilize HIF-1α by binding to hydroxylation site, preventing its degradation and promoting downstream mitochondrial dysfunction.