Zingiberensis new saponin reverses sorafenib resistance by targeting lncRNA TCONS-00026762/AKR1C1 and modulating autophagy and ferroptosis in hepatocellular carcinoma.

[INTRODUCTION] Zingiberensis new saponin (ZnS) extracted from Dioscorea zingiberensis has antitumor activity. Our previous study found that Zns could exert anti- hepatocellular carcinoma (HCC) effects by regulating lncRNA TCONS-00026762. In addition, lncRNA TCONS-00026762 may act synergistically with AKR1C1. However, the relationship between them and their specific molecular mechanism underlying the anti-HCC effects of Zns has not been elucidated. This study aimed to investigate the role of TCONS-00026762/ AKR1C1 axis and ZnS in HCC cells from the perspective of autophagy, ferroptosis, and sorafenib resistance.

[METHODS] Bioinformatics analysis was used to assess the prognostic significance and expression level of AKR1C1 in TCGA liver cancer data. In vitro experiments, the effect of TCONS-00026762 knockdown or Zns on AKR1C1 expression, autophagy, and ferroptosis in HCC cells (Huh7) was investigated. Their function was further confirmed by rescue experiments. In addition, a sorafenib-resistant cell line (Huh7-SR) was constructed to explore the regulatory effects of TCONS-0026762 or Zns on cell viability.

[RESULTS] AKR1C1 was overexpressed in HCC and association with prognosis. It was involved in autophagy and ferroptosis related pathways. TCONS-00026762 knockdown inhibited AKR1C1 expression. TCONS-00026762 knockdown and Zns treatment suppressed the levels of autophagy marker (LC3) and ferroptosis markers (GPX4, SLC7A11) in Huh7 cell, as well as decreased the proliferation and invasion capacities of Huh7-SR cells after sorafenib treatment. Notably, these effects were eliminated by AKR1C1 overexpression or TCONS-00026762 overexpression.

[CONCLUSIONS] Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the TCONS-00026762/AKR1C1 axis.