Alliin from garlic as a neuroprotective agent attenuates ferroptosis <i>in vitro</i> and <i>in vivo via</i> inhibiting ALOX15

Alliin, a precursor active compound of sulfur-containing organic compounds such as allicin in garlic, is recognized as an important bioactive substance in garlic. Allicin has been shown to have significant neuroprotective effects and promote functional recovery in intracerebral hemorrhage (ICH). As a precursor of many active compounds, alliin may have broader therapeutic effects. Therefore, the aim of this study was to investigate the molecular mechanisms underlying the neuroprotective effects of alliin. In this study, we found that alliin inhibits ferroptosis, thereby exerting neuroprotective effects in ICH. However, the neuroprotective effects of alliin and its pharmacological mechanisms in ferroptosis have not been fully explored. The results showed that alliin significantly inhibited erastin-induced ferroptosis in HT22 cells and suppressed ferroptosis in the brain tissue of collagenase-induced ICH mice, alleviating neurological dysfunction and pathological damage. Mechanistically, alliin downregulated the expression of 15-lipoxygenase (ALOX15), which inhibits phospholipid peroxidation and ferroptosis. Moreover, gene knockout of ALOX15 produced effects similar to those of alliin, and comparable results were obtained using the ferroptosis inhibitor ferrostatin-1. This study is the first to demonstrate that alliin regulates ferroptosis both <i>in vitro</i> and <i>in vivo</i>. In conclusion, our study highlights ALOX15 as a critical factor in ferroptosis associated with ICH, and shows that alliin exerts neuroprotective effects by inhibiting ALOX15-dependent ferroptosis.