Background: Hepatocellular carcinoma (HCC), currently ranking as the third most lethal malignancy, poses a grave threat to human health. Ferroptosis, a form of programmed cell demise, has emerged as a promising therapeutic target in HCC treatment. In this study, we investigated the impact of ginsenoside RK1 on ferroptosis induction in HCC cells and elucidated the underlying mechanisms. Methods: The HCC cell line HepG2 was utilized to evaluate the effects of ginsenoside RK1. Distinct dosages of ginsenoside RK1 (25 μM, 50 μM, and 100 μM) were selected based on half-maximal inhibitory concentration (IC50) values. Cellular viability was assessed using a CCK8 assay, cytotoxicity was measured via lactate dehydrogenase (LDH) release assay, and colony-forming ability was evaluated using the clone formation assay. Various inhibitors targeting apoptosis (Z-VAD-FMK 20 μM), necrosis (Nec-1, 10 μM), and ferroptosis (Fer-1, 10 μM; Lip-1, 1 μM) were employed to assess ginsenoside RK1’s impact on cell demise. Intracellular levels of key ions, including glutathione (GSH), malondialdehyde (MDA), and iron ions, were quantified, and the protein expression levels of ferroptosis-related genes were evaluated. The sensitivity of HCC cells to ferroptosis induction by ginsenoside RK1 was examined following the overexpression and silencing of the aforementioned target genes. Results: Ginsenoside RK1 exhibited an inhibitory effect on HCC cells with an IC50 value of approximately 20 μM. It attenuated cellular viability and colony-forming capacity in a dose-dependent manner, concurrently reducing intracellular GSH levels and increasing intracellular Malondialdehyde (MDA) and iron ion contents. Importantly, cell demise induced by ginsenoside RK1 was specifically counteracted by ferroptosis inhibitors. Furthermore, the modulation of Ferroptosis suppressor protein 1 (FSP1) expression influenced the ability of ginsenoside RK1 to induce ferroptosis. FSP1 overexpression or silencing enhanced or inhibited ferroptosis induction by ginsenoside RK1, respectively. Conclusions: Ginsenoside RK1 enhances ferroptosis in hepatocellular carcinoma through an FSP1-dependent pathway.

Hepatocellular carcinoma (HCC) remains the most prevalent primary liver cancer, characterized by alarmingly high mortality rates and low five‐year survival outcomes. A significant challenge in HCC management lies in its advanced‐stage treatment, with most cases identified at advanced, unresectable stages, resulting in poor prognoses and limited treatment options. Over the last decade, considerable advancements have been made in systemic treatment strategies, notably with the introduction of multi‐kinase inhibitors such as sorafenib and lenvatinib, which have redefined the therapeutic landscape for advanced HCC. The emergence of immunotherapy has further revolutionized first‐line treatment, bringing new hope with agents like the PD‐1 inhibitor nivolumab and the CTLA‐4 inhibitor tremelimumab. Moreover, combination regimens such as atezolizumab plus bevacizumab have demonstrated remarkable clinical efficacy, leading to substantial improvements in overall survival and progression‐free survival. Despite the availability of multiple treatment options, clinical trial outcomes remain suboptimal. Key challenges persist in the selection and sequencing of therapies, the development of more diversified combination strategies, and the implementation of downstaging approaches for advanced HCC. This paper aims to provide a comprehensive review of the current progress in systemic therapies for HCC, drawing on extensive research findings and clinical trial data to assess their clinical applications and explore potential challenges. By offering a critical analysis of these therapeutic strategies, this paper seeks to furnish valuable insights and references for ongoing research and future clinical practice, ultimately contributing to improved outcomes in HCC management.