Cadmium (Cd) is a worldwide heavy metal contaminant that unfavorably impacts human fitness, and has the characteristics of widespread existence in eco-systems and irreversible amassing in the body [[1], [2], [3]]. The main routes of Cd entry into the body are the respiratory and digestive tracts mainly through cigarette and food, which are produced from contaminated land and water sources [4,5]. It is well established that Cd accumulates in various organs, especially the kidneys. It is worthwhile to mention that renal tubular cells are considered as a main target of Cd-caused kidney injury [[6], [7], [8]]. Previous research has uncovered that Cd-triggered oxidative stress [[9], [10], [11], [12], [13]] and pyroptosis [14,15] are accounted for nephrotoxicity. However, the mechanism by which Cd-induced pyroptosis still remains ambiguous.

Pyroptosis is a novel type of cell death, distinct from other types of cell death; it is characterized by activation of caspase-1, formation of membrane pore, and leakage of cytoplasm [16]. Cleaved caspase-1 is regulated by inflammasomes, the most canonical type of which is the nod-like receptor family protein 3 (NLRP3) inflammasome [17]. The latest investigation has revealed that the gasdermin D (GSDMD) protein is cleaved by active caspase-1 to form the N-terminal domain (GSDMD-NT), which pores on cellular membrane, then resulting in interleukin-1 beta (IL-1β) and lactate dehydrogenase (LDH) release, causing pyroptosis [18]. Chou et al. showed that Cd triggers NLRP3 inflammasome-dependent pyroptosis, leading to kidney injury in HK-2 cells [14]. Recent reports have brought to light the high association between oxidative stress and pyroptosis during Cd-induced nephrotoxicity. Cd mediates a burst of reactive oxygen species (ROS) production in duck renal tubular epithelial cells and induces pyroptosis via NLRP3/caspase-1 signaling pathway [15]. Moreover, ROS has been well characterized to activate NLRP3 inflammasome [19,20]. Thus, it is necessary to clarify how Cd causes ROS-mediated pyroptosis in Cd-induced kidney injury.

Transcription factor EB (TFEB), a basic helix-loop-helix leucine zipper, is a master mediator for lysosomal biogenesis to enhance autophagic flux, and to regulate cellular homeostasis under the nutrient starvation and oxidative stress conditions [21,22]. It is only in the nucleus that TFEB plays its role, and the activation of TFEB is mainly manifested by translocation to the nucleus, where it recognizes and binds to the CLEAR-box sequence (5′-GTCACGTGAC-3′) to upregulate the expression of autophagy-lysosome-related genes to enhance autophagy [23,24]. Current research has suggested that TFEB is involved in the pathogenesis of kidney injury in multiple conditions, such as diabetic nephropathy and acute kidney diseases [21]. In addition, Li et al. revealed a novel mechanism that carboxyl-modified polystyrene nano-particles decreased the production of ROS in a TFEB-dependent manner [25]. TFEB over-expression decreased overall ROS production in the bovine mammary epithelial cells [26]. To date, there is a lack of data dissecting whether Cd triggers pyroptosis by TFEB-modulated ROS production in nephrotoxicity.

This study aimed to disentangle the mechanism by which Cd exposure induced pyroptosis in renal tubular epithelial cells. The data showed that Cd exposure inhibited TFEB expression and nuclear translocation, which promoted ROS production and further caused the activation of NLRP3, leading to GSDMD cleaving and IL-1β release, and finally inducing pyroptosis. This study provides insight into the mechanism underlying Cd-induced pyroptosis in kidney damage.