Abstract
Background
Long non-coding RNAs (lncRNAs) are often involved in regulating various cellular processes during cancer progression. This study aimed to investigate the role of Zingiberensis new saponin (ZnS) in hepatocellular carcinoma (HCC) cells through the lncRNA TCONS-00026762/AKR1C1 pathway.
Methods
Bioinformatics analysis was initially used to assess the prognostic significance of AKR1C1 in TCGA liver cancer data. Huh7 and Huh7-SR cells were either transfected with sh-TCONS-0026762 and oe-AKR1C1 or treated with ZnS and oe-TCONS-00026762. The expression of TCONS-00026762 and AKR1C1 was quantified using quantitative real-time PCR. The effects of either TCONS-00026762 knockdown or ZnS treatment on autophagy, ferroptosis, and drug sensitivity were investigated using a combination of immunofluorescence staining, western blot, and CCK-8 assays.
Results
Bioinformatics analysis revealed that AKR1C1 is a prognostic marker for HCC and is association with autophagy, ferroptosis, and immune evasion. Knockdown of TCONS-00026762 suppressed autophagy, promoted ferroptosis, and enhanced sensitivity to sorafenib in HCC cells, as evidenced by the decrease in levels of the autophagy marker LC3, as well as ferroptosis markers GPX4 and SLC7A11, and an increase in Huh7-SR cell viability. However, these changes were reversed by overexpression of AKR1C1. Moreover, ZnS treatment significantly downregulated the expression of TCONS-00026762 and AKR1C1, leading to inhibition of autophagy, induction of ferroptosis, and increased susceptibility of HCC cells to sorafenib. Notably, these effects were reversible upon the overexpression of TCONS-00026762.
Conclusions
Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the lncRNA TCONS-00026762/AKR1C1 pathway.