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文章摘要：
Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.
最近的證據(jù)表明，骨關(guān)節(jié)炎的損傷區(qū)域伴隨著鐵離子的積累。鐵下垂作為一種鐵依賴性細(xì)胞死亡形式，在骨關(guān)節(jié)炎中具有重要意義。褪黑素是一種天然產(chǎn)物，具有很強(qiáng)的清除活性氧和脂質(zhì)過(guò)氧化的能力，在骨關(guān)節(jié)炎的治療中起著至關(guān)重要的作用。本研究旨在證明骨關(guān)節(jié)炎中鐵下垂的存在，并探討褪黑素抑制鐵下垂、緩解骨關(guān)節(jié)炎的具體機(jī)制。我們的研究結(jié)果表明，褪黑激素逆轉(zhuǎn)炎癥誘導(dǎo)的氧化應(yīng)激和脂質(zhì)過(guò)氧化，同時(shí)促進(jìn)軟骨細(xì)胞中細(xì)胞外基質(zhì)成分的表達(dá)，保護(hù)細(xì)胞。我們的研究發(fā)現(xiàn)NADPH氧化酶4 (NOX4)在骨關(guān)節(jié)炎的鐵下垂過(guò)程中起著至關(guān)重要的作用。具體來(lái)說(shuō)，NOX4位于軟骨細(xì)胞的線粒體上，可誘導(dǎo)線粒體能量代謝紊亂和功能障礙，從而加劇氧化應(yīng)激和脂質(zhì)過(guò)氧化。LC-MS分析進(jìn)一步發(fā)現(xiàn)GRP78是NOX4的下游結(jié)合蛋白。NOX4通過(guò)削弱GRP78對(duì)GPX4的保護(hù)作用并降低其表達(dá)而誘導(dǎo)鐵下垂。褪黑素可以抑制線粒體NOX4的上調(diào)，減輕線粒體功能障礙，有效抑制鐵下垂，緩解骨關(guān)節(jié)炎。這表明褪黑素治療代表了治療骨關(guān)節(jié)炎的一種有希望的新方法。
