Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Environ Pollut. 2024 Nov 1;360:124764. doi: 10.1016/j.envpol.2024.124764. Epub 2024 Aug 17.
Cigarette smoke (CS) is an important indoor air pollutant associated with an increased risk of ocular surface disease. As the eye's outermost layer, the cornea is highly sensitive to air pollutants like CS. However, the specific mechanisms linking CS exposure to corneal dysfunction have not been fully elucidated. In the present study, we found that CS exposure damages corneal epithelial cells, accompanied by increased iron (Fe) levels and lipid peroxidation, both hallmarks of ferroptosis. Ferroptosis inhibitors, including Ferrostatin-1 (Fer-1) and Deferoxamine mesylate (DFO), protect against CS-induced cell damage. To understand the underlying mechanisms, we investigated how CS affects iron and lipid metabolism. Our results showed that CS could upregulate intracellular iron levels by increasing TFRC expression and promote lipid peroxidation by increasing ACSL4 expression. Silencing ACSL4 or TFRC expression prevented CS-induced ferroptosis. Furthermore, we found that the upregulation of TFRC and ACSL4 was driven by increased YAP transcription. Pharmacological or genetic inhibition of YAP effectively prevented corneal epithelial cell ferroptosis under CS stimulation. Additionally, our results suggest that CS exposure could increase O-GlcNAc transferase activity, leading to YAP O-GlcNAcylation. This glycosylation of YAP interfered with its K48-linked ubiquitination, resulting in YAP stabilization. Collectively, we found that CS exposure induces corneal epithelial cell ferroptosis via the YAP O-GlcNAcylation, and provide evidence that CS exposure is a strong risk factor for ocular surface disease.
香烟烟雾（CS）是一种重要的室内空气污染物，与眼部表面疾病的风险增加有关。作为眼睛的最外层，角膜对 CS 等空气污染物非常敏感。然而，将 CS 暴露与角膜功能障碍联系起来的具体机制尚未完全阐明。在本研究中，我们发现 CS 暴露会损害角膜上皮细胞，同时伴随着铁（Fe）水平升高和脂质过氧化，这都是铁死亡的标志。铁死亡抑制剂，包括 Ferrostatine-1（Fer-1）和甲磺酸去铁胺（DFO），可以预防 CS 诱导的细胞损伤。为了了解潜在的机制，我们研究了 CS 如何影响铁和脂质代谢。我们的结果表明，CS 可以通过增加 TFRC 表达来增加细胞内铁水平，并通过增加 ACSL4 表达来促进脂质过氧化。沉默 ACSL4 或 TFRC 表达可预防 CS 诱导的铁死亡。此外，我们发现 TFRC 和 ACSL4 的上调是由 YAP 转录增加驱动的。YAP 的药理学或遗传抑制可有效预防 CS 刺激下的角膜上皮细胞铁死亡。此外，我们的结果表明，CS 暴露可增加 O-GlcNAc 转移酶的活性，导致 YAP 的 O-GlcNAc 化。这种 YAP 的糖基化干扰了其 K48 连接的泛素化，导致 YAP 稳定。综上所述，我们发现 CS 暴露通过 YAP 的 O-GlcNAc 化诱导角膜上皮细胞铁死亡，并提供了 CS 暴露是眼部表面疾病的一个强风险因素的证据。
