Zinc ions attenuates iridovirus infection through regulation of ferroptosis pathways

Zinc is widely acknowledged as an inducer of ferroptosis, a type of regulated cell death process. Generally, ferroptosis is known to facilitate viral replication. However, an intriguing aspect is that despite its role in inducing ferroptosis, zinc demonstrates broad-spectrum antiviral activity. This study focused on investigating how zinc ions inhibit the replication of the infectious spleen and kidney necrosis virus (ISKNV; an iridovirus) in mandarin fish (a teleost fish) through zinc influx-dependent ferroptosis activation. RNA-seq, enzyme activity assays, and transmission electron microscopy results revealed that zinc could promote ferroptosis in fish. Single-cell sequencing and in vivo validation confirmed that ISKNV infection triggered host ferroptosis, while pharmacological modulation showed that ferroptosis suppressed viral infection. Delving deeper into the mechanism, it was discovered that the expression of GPX4 and xCT partially reversed the antiviral effect of zinc, suggesting that the xCT/GPX4 axis mediated ferroptosis is a mechanistic participant. In vivo challenge assays further verified that zinc monotherapy reduced mortality by 25% and delayed disease progression, and these effects were abolished by co-treatment with the ferroptosis inhibitor vitamin C. This work sheds light on a zinc-ferroptosis axis as an unconventional antiviral defense, redefining both zinc's immune mechanism and the dual role of ferroptosis in viral infection.