N2L, a novel lipoic acid-niacin dimer, attenuates ferroptosis and decreases lipid peroxidation in HT22 cells

Ferroptosis, a new type of programmed cell death discovered in recent years, plays an important role in many neurodegenerative diseases. N2L is a novel lipoic acid-niacin dimer regulating lipid metabolism with multifunction, including antioxidant effect. It also exerts neuroprotective effects against glutamate- or β-amyloid (Aβ) -induced cell death. Because reactive oxygen species (ROS) play an essential role in ferroptosis, we hypothesize that N2L might protect cells from ferroptosis. Here, we investigated the protective effect of N2L and the underlying mechanism(s) under RAS-selective lethality 3 (RSL3) treatment in HT22 cells. RSL3 decreased the cell viability and induced excessive accumulation of ROS in HT22 cells. N2L pretreatment effectively protected HT22 cells against lipid peroxidation. What's more, N2L recovered glutathione peroxidase 4 (GPX4) expression and blocked the increase of Cyclooxygenase-2 (cox-2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein expressions. Moreover, N2L also significantly prevented Ferritin Heavy Chain 1 (FTH1) from downregulation and maintained iron homeostasis. Finally, N2L pretreatment could decrease c-Jun N-terminal kinase (JNK) / extracellular regulated protein kinases (ERK) activation induced by RSL3. Taken together, our results showed that N2L could protect HT22 cells from RSL3-induced ferroptosis through decreasing lipid peroxidation and JNK/ERK activation. And N2L could be a ferroptosis inhibitor for the therapy of ferroptosis-related diseases, such as Alzheimer's disease.