Cottonseed oil alleviates ischemic stroke injury by inhibiting ferroptosis

Abstract

IntroductionFerroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood–brain barrier (BBB) disruption followed by secondary iron‐loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron‐dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke–induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats.MethodsWe conducted the subcutaneous injection of 1.3 mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion–reperfusion (MCAO‐R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, 68Ga‐citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis‐related indexes.ResultsCSO treatment could significantly ameliorate MCAO‐R‐induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up‐regulated anti‐ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down‐regulating ferroptosis‐related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment.ConclusionCSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.

Single-nucleus transcriptome unveils the role of ferroptosis in ischemic stroke

“…Based on the feature importance ranking and gene KO, we found that ferroptosis suppressor genes Fth1 and Ftl1 could significantly affect the expression of microglia homeostasis genes and activation related genes. Studies have shown that Fth1 and Ftl1, as ferroptosis inhibitory genes, can be significantly up-regulated by Cottonseed oil [ 41 ], Electroacupuncture [ 42 ], Quercetin [ 43 ], Insulin [ 44 ], and Ginkgolide B [ 45 ] to exert neuroprotective effects. This is questionable, because the elevation of Fth1 and Ftl1 is bound to aggravates the activation of microglia.…”

Ferritinophagy and Ferroptosis in Cerebral Ischemia Reperfusion Injury

“…Ferritinophagy is a critical mechanism that contributes to iron overload and lipid peroxidation-induced ferroptosis in neuronal cells, which leads to CIRI. In addition, NRF2 is an important regulator of antioxidants reported that fat-soluble solvent-cottonseed oil (CSO) [108], hyperbaric oxygen [109], and other methods can attenuate CIRI by specific mechanisms related to ferroptosis.…”

“…Folic acid (FA) is an important nutrient in the human body, and FA supplementation reduces the risk of stroke and may also inhibit ferroptosis after CIRI by regulating glutamate carboxypeptidase transcriptional adaptive response [ 107 ]. Furthermore, previous studies have reported that fat-soluble solvent-cottonseed oil (CSO) [ 108 ], hyperbaric oxygen [ 109 ], and other methods can attenuate CIRI by specific mechanisms related to ferroptosis.…”

Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke

“…Treatment against ischemic stroke by targeting ferroptosis has gained much attention. 192 Vitexin, 193 Angong Niuhuang Wan, 194 selenium, 195 Srs11‐92, 196 Se‐methyl L‐selenocysteine, 197 Rehmannioside A, 166 Icariside II, 198 Galangin, 199 Carvacrol, 200 Carthamin yellow, 201 β‐Caryophyllene, 202 Astragaloside IV, 203 Salvia miltiorrhiza, 204 Naotaifang extract, 133 Naotaifang, 205 Baicalein, 154 Caffeic acid, 206 Danlou tablet, 207 Rhein, 208 HSYA and AHSYB, 209 Calycosin, 159 Ferrostatin‐1, 210 Compound Tongluo Decoction, 211 Loureirin C, 212 Edaravone, 191 Quercetin, 213 Cottonseed oil, 214 DHT, 215 Dl‐3‐n‐butylphthalide, 216 Dimethyl fumarate, 217 2‐(1‐(4‐(4‐methylpiperazin‐1‐yl)phenyl)ethyl)‐10H‐phenothiazine, 218 Kaempferol, 219 Danhong injection, 220 Neutral polysaccharide from Gastrodia elata , 221 Resveratrol 190 alleviate injury after IS by inhibiting ferroptosis (Table 1 ).…”