Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis
Year: 2025
Type: article
Abstract: 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 sulfonamides 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. • Novel bis(dimethoxybenzylidene)oxocyclohexylsulfonamides and sulfonamides were synthesized as NRF1 activators. • NRF1 activation was confirmed using a luciferase reporter cell line containing an NRF1-responsive construct. • The protective effects of NRF1 activators against ferroptosis inducers were evaluated in SH-SY5Y neuroblastoma cells.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,880
OpenAlex ID: W4414824451