TRPML1 contributes to antimony-induced nephrotoxicity by initiating ferroptosis via chaperone-mediated autophagy.

Evidence suggests that ferroptosis participates in kidney injury. However, the role of ferroptosis in antimony (Sb) induced nephrotoxicity and the mechanism are unknown. Here, we demonstrated that Sb induced injury in renal tubular epithelial cells (RTECs) and ferroptosis. Inhibition of ferroptosis reduced RTECs injury. Besides, elimination of reactive oxygen species (ROS) alleviated ferroptosis and RTECs injury. Moreover, exposure to Sb not only increased the co-localization of glutathione peroxidase 4 (GPX4) and LAMP1, but also decreased the levels of MEF2D and LRRK2, while increased the levels of HSC70, HSP90, and LAMP2a. These findings suggest that Sb activates chaperone-mediated autophagy (CMA), enhances lysosomal transport and subsequent degradation of GPX4, ultimately leads to ferroptosis. Additionally, up-regulation of lysosomal cationic channel, TRPML1, mitigated RTECs injury and ferroptosis. Mechanistically, up-regulation of TRPML1 mitigated the changes in CMA-associated proteins induced by Sb, diminished the binding of HSC70, HSP90, and TRPML1 with LAMP2a. Furthermore, NAC restored the decreased TRPML1 level caused by Sb. In summary, deficiency of TRPML1, secondary to increased ROS induced by Sb, facilitates the CMA-dependent degradation of GPX4, thereby leading to ferroptosis and RTECs injury. These findings provide insights into the mechanism underlying Sb-induced nephrotoxicity and propose TRPML1 as a promising therapeutic target.