Tetrahydrocurcumin Attenuates Polymyxin B Sulfate‐Induced HK‐2 Cells Apoptosis by Inhibiting Endoplasmic Reticulum Stress‐Mediated PERK/eIF2α/ATF4/CHOP Signaling Pathway Axis

ABSTRACT 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.