NDUFS4基因的特異性敲低揭示了uvb誘導的光老化中鐵下沉的重要作用

2024年5月，1浙江省人民醫院皮膚科整形重建外科中心，杭州醫學院附屬人民醫院;2蚌埠醫學院臨床醫學研究生院;3阿克蘇市**人民醫院皮膚科（1Center for

Plastic & Reconstructive Surgery, Department ofDermatology, Zhejiang Provincial People’s Hospital, Afliated People’s Hospital of
Hangzhou Medical College,2Graduate School ofClinical Medicine, Bengbu Medical College,3Department ofDermatology, the First People’s Hospital of
Aksu）Youming Huang and Yibin Fan研究團隊在《Inflammation》上發表論文：

“Specific Knockdown of the NDUFS4 Gene Reveals Important Roles of Ferroptosis in UVB-induced Photoaging”

“NDUFS4基因的特異性敲低揭示了uvb誘導的光老化中鐵下沉的重要作用”

Abstract：

Ultraviolet (UV) irradiation significantly contributes to photoaging. Ferroptosis, an iron-dependent cell death mode recently identified, plays a key role in UVB-induced skin photoaging. This study examines the functions and regulatory mechanisms of ferroptosis in this regard.

Characterized by increased intracellular iron and reactive oxygen species (ROS), ferroptosis is associated with mitochondrial function and structure. Through RNA sequencing, we identified NADH: ubiquinone oxidoreductase subunit S4 (NDUFS4), a gene implicated in UVB-mediated photoaging, and explored its role in ferroptosis by NDUFS4 knockdown. In vitro, inhibiting NDUFS4 reduced ferroptosis, decreased ROS and matrix metallopeptidase 1 levels, and increased collagen type I alpha 1 chain, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1, and solute carrier family 7 member 11 levels, suggesting a reinforced ferroptosis protective mechanism.

Additionally, NDUFS4 regulates ferroptosis via the mitogen-activated protein kinase (MAPK) pathway, with its knockdown reducing p38 and ERK phosphorylation and elevating GPX4 levels, enhancing ferroptosis resistance. Animal experiments supported these findings, demonstrating that Ferrostatin-1, a ferroptosis inhibitor, significantly mitigated UVB-induced skin photoaging and related protein expression. This study uncovers NDUFS4’s novel role in regulating ferroptosis and provides new insights into ferroptosis-mediated UVB-induced skin photoaging.

摘要：

紫外線(UV)照射顯著地促進光老化。最近發現的鐵依賴性細胞死亡模式鐵凋亡在uvb誘導的皮膚光老化中起關鍵作用。本研究探討了鐵下垂在這方面的功能和調節機制。以細胞內鐵和活性氧(ROS)增加為特征，鐵下垂與線粒體功能和結構有關。通過RNA測序，研究確定了與uvb介導的光老化有關的NADH:泛醌氧化還原酶亞基S4 (NDUFS4)基因，并通過敲低NDUFS4來探索其在鐵死亡中的作用。在體外，抑制NDUFS4可降低鐵下垂，降低ROS和基質金屬肽酶1水平，增加I型膠原α 1鏈、谷胱甘肽過氧化物酶4 (GPX4)、鐵蛋白重鏈1和溶質載體家族7成員11水平，提示鐵下垂保護機制增強。此外，NDUFS4通過絲裂原活化蛋白激酶(MAPK)途徑調控鐵下垂，其敲低可降低p38和ERK磷酸化，提高GPX4水平，增強鐵下垂抗性。動物實驗支持這些發現，表明Ferrostatin-1，一種鐵下垂抑制劑，顯著減輕uvb誘導的皮膚光老化和相關蛋白的表達。這項研究揭示了NDUFS4在調控鐵凋亡中的新作用，并為鐵凋亡介導的uvb誘導的皮膚光老化提供了新的見解。

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