Paraquat (PQ) is a non-selective herbicide that is widely used owing to its low cost and high efficiency [1]. However, PQ is extremely toxic to humans [2]. Although the production of aqueous PQ agents has been banned, powder forms remain in use. Therefore, PQ poisoning is a common problem in developing countries. Importantly, PQ toxicity can impact multiple organs, including the lungs, kidneys, and liver [3,4]. High PQ concentrations have been found to accumulate in the kidneys and can cause severe nephrotoxicity [5]. Renal damage and decreased renal function may further impair PQ elimination, ultimately resulting in multiorgan failure [6]. Moreover, the absence of specific antidotes against PQ toxicity has resulted in high mortality rates. Despite considerable efforts to elucidate the related toxicity mechanisms, molecular mechanisms underlying PQ poisoning remain elusive. Therefore, to successfully treat PQ poisoning, it is essential to alleviate PQ-induced acute kidney injury and maintain good renal function.

Pyroptosis is defined as a gasdermin-mediated programmed cell death characterized by the formation of cell membrane pores and the extravasation of cellular content. Gasdermin D (GSDMD) is a key mediator of pyroptosis. It has been reported that active caspase1 cleaves GSDMD, and the cleaved N domain of GSDMD induces pore formation in the cell membrane [7]. Additionally, pyroptosis has been shown to contribute to sepsis-induced acute kidney injury [8,9], and participates in the development of drug-induced kidney injury [10]. However, the role of GSDMD-mediated pyroptosis in PQ-induced kidney injury remains unclear.

Mitochondria are crucial cellular organelles, and the excessive accumulation of mitochondrial reactive oxygen species (ROS-induced mitochondrial dysfunction) plays an important role in the pathogenesis of several diseases [11,12]. Recently, PQ was shown to increase ROS accumulation and damage mitochondria [13,14]. Mitoquinone (MitoQ), which comprises coenzyme Q10 and triphenylphosphonium (TPP) cations, is a mitochondria-targeted antioxidant [15]. Reportedly, MitoQ may afford protection against liver cirrhosis and acute lung injury by ameliorating oxidative stress [16,17]. Furthermore, MitoQ reportedly ameliorates tubular injury in diabetic kidney disease [18]. Accordingly, we examined whether MitoQ supplementation could be an effective treatment to combat PQ poisoning.

In the current study, we investigated the role of GSDMD-mediated pyroptosis in PQ-induced nephrotoxicity. We also explored the potential mechanism of mitochondrial ROS production, which leads to pyroptosis via the activation of p38-mitogen-activated protein kinase (MAPK) signaling. In addition, MitoQ was used to alleviate the PQ-induced acute kidney injury.