Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis

Ferroptosis is a regulated form of cell death characterized by lipid peroxidation and excessive reactive oxygen species (ROS) accumulation, which are driven primarily by iron dysregulation. It plays a critical role in neurodegeneration, cancer, and ischaemia-reperfusion injury, making its modulation a promising therapeutic strategy. NFE2L1 (nuclear factor erythroid 2-related factor 1) is a key transcription factor in cellular homeostasis that mitigates oxidative and proteotoxic stress by regulating antioxidant, cytoprotective and proteostasis-related genes. In this study, we designed and synthesized a series of bis(dimethoxybenzylidene)oxocyclohexylsulfonamides and sulfamides that robustly activate NFE2L1. At low micromolar concentrations, these compounds protect human neuroblastoma SH-SY5Y cells from the ferroptosis-inducing agents erastin, RSL3, and ferric ammonium citrate (FAC)-induced oxidative cell death, demonstrating their potential as NFE2L1-targeting cytoprotective agents.