Latency-associated nuclear antigen (LANA) promotes ferroptosis by suppressing Nrf2 and upregulating MDM2

Ferroptosis is a recently discovered iron-dependent form of programmed cell death, characterized by the accumulation of lipid peroxidation. Latency-associated nuclear antigen (LANA) plays a crucial role in ensuring the survival and proliferation of cells infected with Kaposi’s sarcoma-associated herpesvirus (KSHV). In this study, we investigated the effects of LANA on ferroptosis. Surprisingly, we discovered that LANA promotes ferroptosis, with its downregulation diminishing and upregulation enhancing this process. LANA itself did not alter intracellular reactive oxygen species (ROS) levels; it modulated ROS levels in response to ferroptosis inducers. Cells with reduced LANA levels exhibited significantly elevated ROS levels, whereas cells overexpressing LANA showed lower ROS levels. LANA suppressed the expression of genes crucial for ferroptosis resistance, such as glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Additionally, LANA inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) expression, impeding its nuclear translocation, while upregulating the expression of mouse-double minute 2 (MDM2). Inhibitors targeting Nrf2 and MDM2 partially negated the effects of LANA knockdown and overexpression, respectively, on ferroptosis. These findings suggested that LANA promotes ferroptosis and implyed that inducing ferroptosis may represent a new therapeutic strategy in treating KSHV-related tumors.