The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB‐induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB‐induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB‐induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB‐induced nephrotoxicity in an in vitro model of PMB‐induced cell injury. Moreover, we demonstrated that THC effectively protected HK‐2 cells from PMB‐induced apoptosis by using cell counting kit‐8 and flow cytometry assay. THC could also suppress PMB‐induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB‐induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB‐induced nephrotoxicity by inhibiting the ER stress‐mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB‐induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.

中文翻译：

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四氢姜黄素通过抑制内质网应激介导的 PERK/eIF2α/ATF4/CHOP 信号通路轴来减弱硫酸多粘菌素 B 诱导的 HK-2 细胞凋亡


多粘菌素 B （PMB） 的临床应用受其肾毒性作用的限制，使得降低 PMB 诱导的肾毒性成为临床医生迫切关注的问题。四氢姜黄素 （THC） 以其在生物学功能方面的有益特性而闻名，为减轻 PMB 诱导的肾毒性的干预治疗提供了一种有吸引力的选择。然而，THC 如何减轻 PMB 诱导的肾毒性的潜在机制仍然知之甚少。在这里，我们首先在 PMB 诱导的细胞损伤的体外模型中评估了 THC 干预疗法减轻 PMB 诱导的肾毒性的潜力。此外，我们证明 THC 通过使用细胞计数试剂盒 8 和流式细胞术测定有效保护 HK-2 细胞免受 PMB 诱导的细胞凋亡。THC 还可以通过 PERK/eIF2α/ATF4/CHOP 通路抑制 PMB 诱导的内质网 （ER） 应激。此外，使用 PERK 抑制剂 GSK2606414 抑制 ER 应激也减轻了 PMB 诱导的细胞凋亡。综上所述，这些发现提供了新的见解，即 THC 具有通过抑制 ER 应激介导的 PERK/eIF2α/ATF4/CHOP 轴来减轻 PMB 诱导的肾毒性的能力，这阐明了 THC 作为减少 PMB 诱导的肾毒性的干预策略的好处，从而为改善接受 PMB 治疗的患者的临床结果提供了一条潜在的途径。