Intracerebral haemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. It has been reported that paeonol (PAN) inhibits the progression of ICH. However, the mechanism by which paeonol mediates the progression of ICH remains unclear. To mimic ICH in vitro, neuronal cells were treated with hemin. An in vivo model of ICH was established to detect the effect of paeonol on ferroptosis in neurons during ICH. Cell viability was tested by MTT assay. Furthermore, cell injury was detected by GSH, MDA and ROS assays. Ferroptosis was examined by iron assay. RT-qPCR and western blotting were used to detect gene and protein expression, respectively. The correlation among HOTAIR, UPF1 and ACSL4 was explored by FISH, RNA pull-down and RIP assays. Paeonol significantly inhibited the ferroptosis of neurons in ICH mice. In addition, paeonol significantly reversed hemin-induced injury and ferroptosis in neurons, while this phenomenon was notably reversed by HOTAIR overexpression. Moreover, paeonol notably inhibited ferroptosis in hemin-treated neuronal cells via inhibition of ACSL4. Additionally, HOTAIR bound to UPF1, and UPF1 promoted the degradation of ACSL4 by binding to ACSL4. Furthermore, HOTAIR overexpression reversed paeonol-induced inhibition of ferroptosis by mediating the UPF1/ACSL4 axis. Paeonol inhibits the progression of ICH by mediating the HOTAIR/UPF1/ACSL4 axis. Therefore, paeonol might serve as a new agent for the treatment of ICH.

脑出血（ICH）是一种破坏性的中风亚型，具有很高的发病率和死亡率。据报道，丹皮酚 (PAN) 可抑制 ICH 的进展。然而，丹皮酚介导ICH进展的机制仍不清楚。为了在体外模拟 ICH ，用氯化血红素处理神经元细胞。建立ICH体内模型，检测丹皮酚对ICH期间神经元铁死亡的影响。通过MTT法检测细胞活力。此外，通过 GSH、MDA 和 ROS 检测检测细胞损伤。通过铁测定检查铁死亡。RT-qPCR和蛋白质印迹分别用于检测基因和蛋白表达。通过 FISH、RNA pull-down 和 RIP 检测探讨了 HOTAIR、UPF1 和 ACSL4 之间的相关性。丹皮酚显着抑制ICH小鼠神经元的铁死亡。此外，丹皮酚可显着逆转血红素诱导的神经元损伤和铁死亡，而 HOTAIR 过表达可显着逆转这种现象。此外，丹皮酚通过抑制 ACSL4 显着抑制经氯化血红素处理的神经元细胞中的铁死亡。此外，HOTAIR 与 UPF1 结合，UPF1 通过与 ACSL4 结合促进 ACSL4 的降解。此外，HOTAIR 过表达通过介导 UPF1/ACSL4 轴逆转丹皮酚诱导的铁死亡抑制。丹皮酚通过介导 HOTAIR/UPF1/ACSL4 轴来抑制 ICH 的进展。因此，丹皮酚可能成为治疗脑出血的新药。