MiR-330-3p promotes T cell ferroptosis and IFN-γ production via targeting NAT10 in neurosyphilis

MicroRNAs, particularly miR-330-3p, are fundamentally involved in many infectious diseases and the host's response to pathogen attacks, with previous studies noting increased miR-330-3p levels in neurosyphilis patients' PBMCs compared to healthy controls. The detailed biological functions and mechanisms of miR-330-3p in neurosyphilis, however, remain poorly defined. Our research confirms elevated miR-330-3p expression in CD4⁺ T cells of neurosyphilis patients, correlating significantly with T cell ferroptosis. Using bioinformatic predictions and in vitro cell experiments, including gene overexpression, silencing, and ac4C dot plot, in human Jurkat-E6-1 and primary CD4⁺ T cell, we have shown that miR-330-3p binds to the 3'UTR of NAT10 mRNA, overexpression of miR-330-3p could significantly suppress NAT10 expression, which in turn leads to decreased acetylation of GPX4 mRNA and increased T cell ferroptosis due to reduced glutathione peroxidase activity. Overexpression of NAT10 or activation of GPX4 Glutathione Peroxidase activity could obviously reverse the elevated T cell ferroptosis induced by miR-330-3p overexpression. Additionally, our findings demonstrate that miR-330-3p enhances IFN-γ production in a NAT10-independent manner. These results unveil a novel mechanism through which miR-330-3p promotes T cell ferroptosis and IFN-γ production in neurosyphilis.