Exposure to Alcohol Causes Ferroptosis Activation Associated with Suppression of Heat Shock Responses-mediated iron metabolism disorder in Caenorhabditis elegans

Exposure to alcohol caused toxicity in Caenorhabditis elegans (C. elegans). However, the underlying mechanisms for this induced toxicity by alcohol remain largely unclear. We examined possible association of ferroptosis activation with toxicity of alcohol. This study revealed that alcohol (400 mM-700 mM)-related iron toxicity suppressed head thrash, pharyngeal pumping of C. elegans, generated reproductive toxicity and oxidative stress, while rescued by ferroptosis inhibitor Fer-1(100 μmol/L) and iron chelating agent DFO (50 μmol/L). Meanwhile, alcohol resulted in increased Fe²⁺ levels due to iron metabolism dysfunction, promoting iron uptake by increasing gene level of Smf-3, suppressing iron storage and efflux by decreasing gene level of Ftn-1 and Fpn-1.1. Besides, alcohol caused increased MDA content, decreased GSH content, as well as alterations in the expression Gpx-1, Ftn-1, and Acs-17, facilitating ferroptosis. Moreover, alcohol-caused shorten lifespan, abnormal physiological state, reproductive toxicity as well as disturbed iron homeostasis and ferroptosis were all exacerbated in hsf-1 and skn-1 mutation C. elegans. The study offers novel insights into the mechanisms of alcohol-induced iron metabolism dysfunction and ferroptosis in C. elegans.