Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of human cancers. However, the nephrotoxicity of cisplatin limits its use as a therapeutic agent. It has been suggested that oxidative stress and p53 activation play important roles in cisplatin-induced nephrotoxicity. It has been demonstrated that the eukaryotic translation initiation factor 2α (eIF2α) may protect HK-2 human renal proximal tubular cells against cisplatin-induced apoptosis through inhibition of reactive oxygen species (ROS)‑mediated p53 activation. The aim of the present study was to investigate the effects of siRNA‑mediated knockdown of the PKR-like endoplasmic reticulum kinase (PERK) gene, which induces the phosphorylation of eIF2α, or Sal003, a selective inhibitor of eIF2α dephosphorylation, on cisplatin‑induced apoptosis in HK-2 cells. Cisplatin induced eIF2α phosphorylation as well as p53 activation. In particular, inhibition of p53 by pifithrin‑α, and upregulation of eIF2α phosphorylation by Sal003, reduced cisplatin-induced apoptosis. Of note, Sal003‑mediated upregulation of eIF2α phosphorylation suppressed cisplatin‑induced p53 activation. Furthermore, reduction of eIF2α phosphorylation by PERK knockdown enhanced cisplatin-induced p53 activation and apoptosis. In addition, the ROS scavenger N-acetyl-L-cysteine inhibited eIF2α phosphorylation as well as p53 activation in HK-2 cells treated with cisplatin, suggesting that oxidative stress induced by cisplatin may lead to apoptosis through p53 activation; furthermore, this stress may confer resistance to apoptosis via eIF2α phosphorylation, which was further supported by the finding that cisplatin‑induced ROS generation was attenuated by Sal003, whereas it was enhanced by PERK knockdown. Furthermore, cisplatin induced the expression of activating transcription factor 4 (ATF4) and heme oxygenase-1 (HO-1) that were enhanced by Sal003 and reduced by PERK knockdown. Taken together, these results suggest that phosphorylation of eIF2α suppresses cisplatin‑induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in HK-2 cells, as ATF4 expression is usually dependent on the phosphorylation of eIF2α and may also transcriptionally induce the expression of HO-1 in response to oxidative stress. Therefore, regulation of eIF2α phosphorylation may play an important role in alleviating cisplatin-induced nephrotoxicity.