Zhao Hongmin, Li Renlin, Guo Xuan, Kang Jingrui, Li Huajun, Wang Xiaoyun, Wang Yuansong, Cui Huantian, Lv Shuquan, Wen Weibo, Zhang Zhongyong
Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China.
Yunnan University of Chinese Medicine, Kunming, China.
PLoS One. 2025 Jun 20;20(6):e0325674. doi: 10.1371/journal.pone.0325674. eCollection 2025.
Pancreatic β-cell damage, a key pathology in Type 2 Diabetes Mellitus (T2DM), may be mitigated by inhibiting ferroptosis. Plantamajoside (PMS) shows promise in alleviating cellular damage and improving T2DM outcomes, though its mechanisms remain unclear. This study investigated PMS's role in suppressing ferroptosis in pancreatic β-cells via the cysteine/glutamate transporter (xCT)/ glutathione peroxidase 4 (GPX4) pathway. In our in vivo experiments, PMS was administered to T2DM mice via gavage, and its effects on tissue damage, ferroptosis, and xCT/GPX4 pathway modulation were assessed. Furthermore, in vitro experiments employed high glucose (HG) and palmitic acid (PA) conditions, to induce damage in pancreatic β-cells. We investigated the beneficial impacts of PMS on pancreatic β-cell damage, its modulation of ferroptosis, and its influence on the xCT/GPX4 pathway. To compare the capacity of PMS to inhibit ferroptosis, we utilized the ferroptosis inhibitor ferrostatin-1 (Fer-1) as a positive control, while the GPX4 inhibitor RSL-3 validated PMS's mechanism through the xCT/GPX4 axis. Our findings revealed that PMS effectively mitigated pancreatic tissue damage in T2DM mice, reduced ferroptosis, and enhanced the expression of factors associated with the xCT/GPX4 pathway. Moreover, PMS alleviated HG and PA-induced damage in pancreatic β-cells, suppressed ferroptosis, and upregulated factors linked to the xCT/GPX4 pathway. Similar to the ferroptosis inhibitor Fer-1, PMS exhibited comparable effects. Conversely, RSL-3 attenuated the protective effects of PMS on pancreatic β-cell damage, its inhibition of ferroptosis, and its activation of the xCT/GPX4 pathway. PMS exhibited the capacity to diminish damage to pancreatic islet β-cells induced by T2DM, both in vivo and in vitro. This favorable outcome may stem from the alleviation of lipid peroxidation and reduction of ferroptosis. Moreover, this regulatory mechanism was accomplished through the enhancement of the xCT/GPX4 axis.
胰腺β细胞损伤是2型糖尿病（T2DM）的关键病理特征，抑制铁死亡可能会减轻这种损伤。Plantamajoside（PMS）在减轻细胞损伤和改善T2DM结局方面显示出前景，但其机制尚不清楚。本研究通过半胱氨酸/谷氨酸转运体（xCT）/谷胱甘肽过氧化物酶4（GPX4）途径，研究了PMS在抑制胰腺β细胞铁死亡中的作用。在我们的体内实验中，通过灌胃给T2DM小鼠施用PMS，并评估其对组织损伤、铁死亡和xCT/GPX4途径调节的影响。此外，体外实验采用高糖（HG）和棕榈酸（PA）条件，诱导胰腺β细胞损伤。我们研究了PMS对胰腺β细胞损伤的有益影响、其对铁死亡的调节及其对xCT/GPX4途径的影响。为了比较PMS抑制铁死亡的能力，我们使用铁死亡抑制剂ferrostatin-1（Fer-1）作为阳性对照，而GPX4抑制剂RSL-3通过xCT/GPX4轴验证了PMS的机制。我们的研究结果表明，PMS有效地减轻了T2DM小鼠的胰腺组织损伤，减少了铁死亡，并增强了与xCT/GPX4途径相关的因子的表达。此外，PMS减轻了HG和PA诱导的胰腺β细胞损伤，抑制了铁死亡，并上调了与xCT/GPX4途径相关的因子。与铁死亡抑制剂Fer-1相似，PMS表现出类似的效果。相反，RSL-3减弱了PMS对胰腺β细胞损伤的保护作用、其对铁死亡的抑制作用以及对xCT/GPX4途径的激活作用。PMS在体内和体外均表现出减少T2DM诱导的胰岛β细胞损伤的能力。这一良好结果可能源于脂质过氧化的减轻和铁死亡的减少。此外，这种调节机制是通过增强xCT/GPX4轴来实现的。
