Immunomodulatory effects of 4-hydroxynonenal

The reactive aldehyde 4-hydroxy-2-nonenal (4-HNE) is a byproduct of lipid peroxidation driven by reactive oxygen species (ROS). 4-HNE covalently binds to macromolecules such as proteins, altering their functions. While 4-HNE is implicated in various ROS-related pathologies, its impact on the immune system remains incompletely understood. This review explores how 4-HNE influences molecular mechanisms involved in inflammation and immune cell functions. 4-HNE modulates inflammation through the interaction with several signaling pathways, including nuclear factor kappa-light-chain enhancement of activated B cells (NF-κB), nuclear factor erythroid 2-related factor (Nrf2), mitogen-activated protein kinases (MAPK), toll-like receptor (TLR) 4, and stimulator of interferon genes (STING), thereby affecting immune responses and modulating cytokine production and inflammasome activation. However, its effects are complex, exhibiting both pro- and anti-inflammatory properties depending on dose and cell type. This review highlights the multiple mechanisms by which 4-HNE modulates the immune cells' responses.