Hemocyanin modulates ferroptosis through a HSP90-dependent antioxidant function in shrimp

Ferroptosis, an iron-dependent programed cell death, is essential for maintaining homeostasis and responding to environmental and pathogenic stressors in mammals. In shrimp, ferroptosis is also vital in various biological processes, including stress response and immunity. However, the specific regulatory mechanisms of ferroptosis in shrimp and other marine animals remains unclear. In this study, we demonstrate that hemocyanin actively modulates ferroptosis in the hepatopancreas of Penaeus vannamei, exhibiting a significant inhibitory effect through its small subunit. During ferroptosis, shrimp show reduced expression of GPX4 and depletion of hemocyanin. Importantly, we identified a novel interaction between hemocyanin and heat shock protein 90 (HSP90), in which HSP90 acts as a molecular partner for hemocyanin to reduce reactive oxygen species (ROS) during ferroptosis. Depletion of either hemocyanin and HSP90 results in elevated ferrous iron (Fe²⁺) and lipid peroxidation levels, along with reduced cell viability. These findings reveal the central role of hemocyanin in enhancing shrimp resilience to oxidative damage and suggest its potential as a therapeutic target in aquaculture to improve immunity and survival under environmental stress.