Due to global climate change and growing environmental pollution, the likelihood of mycotoxin contamination in food and crops has considerably increased. Zearalenone (ZEA), one of the common mycotoxins, is produced by Fusarium fungi and is frequently encountered in grains such as corn, wheat and barley [[1], [2], [3]]. It has estrogenic effects, mimicking the hormone estrogen in animals, which can lead to reproductive toxic effects ([[3], [4], [5]]). ZEA contamination is a concern in agriculture as it poses risks to livestock health, affecting their fertility and overall well-being as well as humans.

ZEA can cause a range of toxic effects including reproductive issues such as infertility, abnormal uterine growth, and early puberty, and developmental disturbances in experimental animals, particularly due to its estrogen-like properties, which interfere with hormonal balance [3,[6], [7], [8]]. Additionally, ZEA induces immunotoxic, hepatotoxic, and nephrotoxic effects through inflammation, oxidative damage, endoplasmic reticulum (ER) stress, and apoptosis via the p53-dependent mitochondrial signaling pathway [1,[9], [10], [11], [12], [13], [14], [15], [16], [17]]. So, stress response signaling appears to contribute to ZEA-induced toxicity. Exposure to ZEA has been linked to liver and kidney damage, leading to liver lesions and progressive nephropathy both in vivo and in vitro [6,15,[17], [18], [19], [20], [21], [22]]. In line with these data, ZEA is classified as a Group 3 carcinogen by The International Agency for Research on Cancer (IARC) [23]. Although ZEA could exert genotoxic properties through chromosomal aberrations, micronucleus formation, DNA adducts and breakage, several existing studies indicate that it also leads to epigenetic modifications by DNA methylation and histone modifications [[24], [25], [26], [27], [28], [29], [30], [31], [32]]. Also, there are limited studies that show ZEA exposure can alter the miRNA expression profiles [[33], [34], [35], [36], [37], [38], [39]].

Apoptosis, or programmed cell death, is a critical process that helps maintain cellular homeostasis by eliminating damaged cells. ER stress occurs when there is an accumulation of misfolded proteins within the ER and this stress activates various signaling pathways, including the unfolded protein response (UPR), to restore normal cellular conditions [40]. The ER stress upregulates molecular chaperones such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP, also known as DNA damage-inducible transcript 3) which also acts as an apoptotic transcriptional factor [41]. GRP78 interacts with inositol requiring enzyme 1 (IRE1) and pancreatic ER kinase (PERK); after that, the activated PERK mediates the stress response through eukaryotic initiation factor 2α (eIF2α) and activating transcription factor (ATF)-4, all of which play a vital role for ER stress [42]. However, prolonged or excessive ER stress can trigger apoptosis to prevent further damage [43]. So, ER stress-induced apoptosis involves several key proteins, including CHOP and caspases (caspase-3 (CASP3), caspase-9 (CASP9), etc.), that mediate the cell's decision to undergo programmed death. Taken together, ER stress is multifaceted and also acts on aspects at the epigenetic level, including transcriptional and post-translational levels. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various diseases. Based on the findings of the present study, exploring the role of miRNAs, histone modifications, and their relationship with ER stress in response to ZEA exposure could be important in elucidating the mechanism of ZEA-induced nephrotoxic effects.

Human embryonic kidney (HEK-293) cell lines offer an in vitro model for nephrotoxicity that is highly versatile [[44], [45], [46]]. The present study aims to detect the effects of ZEA on ER stress, which could be related mechanisms contributing to ZEA-induced toxicity, whether this process is related to epigenetic modifications such as global and gene-specific histone modifications and miRNA regulations in HEK-293 cells.