Wipplinger A, Bekric D, Ablinger C, Kittl M, Mayr C, Ritter M, Winklmayr M, Jakab M
Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Salzburg, Austria.
J Cell Mol Med. 2025 Jul;29(13):e70592. doi: 10.1111/jcmm.70592.
The present study investigates the effects of cannabidiol (CBD), the major non-psychoactive compound of Cannabis sativa L. extracts, on ferroptotic cell death in human articular chondrocytes. Exposure to known ferroptosis inducers RSL3, erastin and its analogue IKE, FINO2 and FIN56 led to a varying extent of reduced cell viability in two chondrocyte cell lines (in C-28/I2, T/C-28/A2) and primary chondrocytes, suggesting different sensitivity and defence mechanisms towards the respective substances. The cytotoxic effects were aggravated by additional exposure to iron and inhibited by the specific ferroptosis inhibitor ferrostatin-1 (Fer-1), proving the occurrence of ferroptosis. Strikingly, co-treatment of ferroptosis inducers with CBD clearly restored cell viability in a dose-dependent manner (10 nM to 1 μM CBD) in both cell lines and primary chondrocytes. Moreover, CBD restored the activity of GPX4, a major anti-oxidative enzyme, to varying degrees when combined with IKE or RSL3. Increasing evidence has emerged for an important role of iron dyshomeostasis and ferroptosis in the onset and progression of various orthopaedic diseases, including osteoarthritis. Therefore, the here demonstrated and previously unreported cytoprotective and anti-oxidative effects of CBD in the context of ferroptosis have highly promising therapeutic implications.
本研究调查了大麻素（CBD），即大麻提取物的主要非精神活性化合物，对人关节软骨细胞铁死亡的影响。已知的铁死亡诱导剂RSL3、埃拉斯汀及其类似物IKE、FINO2和FIN56暴露导致两种软骨细胞系（C-28/I2、T/C-28/A2）和原代软骨细胞的细胞活力不同程度降低，表明对各自物质的敏感性和防御机制不同。额外暴露于铁会加重细胞毒性作用，而特异性铁死亡抑制剂铁抑素-1（Fer-1）可抑制该作用，证明了铁死亡的发生。引人注目的是，在两种细胞系和原代软骨细胞中，铁死亡诱导剂与CBD共同处理均能以剂量依赖方式（10 nM至1 μM CBD）显著恢复细胞活力。此外，当与IKE或RSL3联合使用时，CBD能不同程度地恢复主要抗氧化酶GPX4的活性。越来越多的证据表明，铁稳态失调和铁死亡在包括骨关节炎在内的各种骨科疾病的发生和发展中起重要作用。因此，本文所证明的且此前未报道的CBD在铁死亡背景下的细胞保护和抗氧化作用具有极具前景的治疗意义。
