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

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2026-02-01 Epub Date: 2025-11-28 DOI:10.1016/j.taap.2025.117664

Liang Luo , Pingsheng Zhou , Keqing He

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引用次数: 0

Abstract

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.

Abstract Image

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姜叶新皂苷通过靶向lncRNA tcon -00026762/AKR1C1并调节肝细胞癌的自噬和铁凋亡逆转索拉非尼耐药。

摘要：从盾叶薯蓣中提取的盾叶新皂苷（ZnS）具有抗肿瘤活性。我们前期研究发现Zns可通过调控lncRNA TCONS-00026762发挥抗肝细胞癌（HCC）作用。此外，lncRNA TCONS-00026762可能与AKR1C1协同作用。然而，它们之间的关系及其在Zns抗hcc中的具体分子机制尚未阐明。本研究旨在从自噬、铁凋亡和索拉非尼耐药的角度探讨lncRNA TCONS-00026762/ AKR1C1和ZnS在HCC细胞中的作用。方法：采用生物信息学分析方法评估AKR1C1在TCGA肝癌资料中的预后意义及表达水平。体外实验研究tcon -00026762敲低或Zns对HCC细胞（Huh7）中AKR1C1表达、自噬和铁凋亡的影响。救援实验进一步证实了其功能。此外，构建索拉非尼耐药细胞株（Huh7-SR），探讨TCONS-0026762或Zns对细胞活力的调控作用。结果：AKR1C1在HCC中过表达并与预后相关。它参与了自噬和铁下垂相关的途径。TCONS-00026762敲低抑制AKR1C1表达。tcon -00026762敲除和Zns处理抑制Huh7细胞自噬标志物（LC3）和铁凋亡标志物（GPX4、SLC7A11）水平，降低索拉非尼处理后Huh7- sr细胞的增殖和侵袭能力。值得注意的是，这些影响被AKR1C1过表达或TCONS-00026762过表达消除。结论：我们的研究结果表明，ZnS通过lncRNA tcon -00026762/AKR1C1轴抑制HCC细胞自噬，促进铁凋亡，并增强对索拉非尼的敏感性。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.