A pre-dose biomarker Ccrn4l for predicting the susceptibility of cisplatin-induced hepatotoxicity

다국어 초록 (Multilingual Abstract)

Cisplatin-induced liver injury is one of the limitations of its use as an anti-cancer drug. In particular, individual differences in sensitivity to drug-induced liver injury (DILI) can lead to life-threatening situations. The purpose of this study is to discover which innate genetic factors determine diversity for susceptibility to DILI. Rats undergo a liver prebiopsy and a 3-week postoperative recovery period prior to cisplatin administration. Two days after administration of cisplatin, hepatotoxicity was confirmed through serum biochemical and histopathological analysis. Based on liver-related biochemical test results (ALT, AST, γGT), rats were sub-grouped into the Susceptible (top five) or Resistant (bottom five) group for RNA sequencing using the pre-collected liver samples. As a result, pre-dose 161 genes were differentially expressed between the susceptible and resistant groups. Among them, Ccrn4l, a clock-controlled gene included in the "rhythmic process", was inherently low in gene expression before drug administration in both cisplatin- and acetaminophen-susceptible animals. In addition, in the susceptible group, the innately low expression level of Ccrn4l was maintained even after cisplatin treatment with decreased antioxidants, increased nitration, and apoptosis. When checking the correlation between Ccrn4l, antioxidant catalase, and mitochondrial RNA in the liver, it was confirmed that they showed similar mRNA expression patterns according to individual circadian variation. Surprisingly, Ccrn4l knockdown WB-F344 cells prompted cisplatin-induced mitochondrial dysfunction, apoptosis, and decreased catalase activity. In conclusion, individual innate hepatic Ccrn4l level may be a novel factor affecting cisplatin-induced hepatotoxicity susceptibility by modulating mitochondrial and antioxidant functions.