AMPD3 promotes doxorubicin-induced cardiomyopathy through HSP90α-mediated ferroptosis.

Doxorubicin (DOX), a widely used anticancer drug, can induce myocardial damage, and current treatments are limited. Our research identified AMPD3 upregulation in DOX-induced cardiotoxicity (DIC), and we hypothesized that AMPD3 may contribute to cardiac injury by regulating mitochondrial dynamics and ferroptosis. We generated AMPD3 knockout (KO) mice and AC16 cell models with AMPD3 knockdown/overexpression, using various methods to explore underlying mechanisms. AMPD3 KO mice showed improved ejection fractions and reduced myocardial injury compared to controls. Transcriptome sequencing revealed reduced HSP90AA1, HSP90B1, ACSL4, and dynamin-related protein 1 (DRP1) levels. We further demonstrated that AMPD3 interacts with HSP90α, activating DRP1, leading to mitochondrial fission, increased reactive oxygen species (ROS) release, and ACSL4-mediated ferroptosis. Our findings suggest inhibiting AMPD3 during DOX treatment may alleviate myocardial damage, highlighting mitochondrial function and ferroptosis as potential therapeutic targets for DIC.