# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Secondary Resistance
#### 1.3.3 Ferroptosis  
Ferroptosis was discovered recently and is a novel type of cell death. Increased iron (Fe) accumulation and lipid peroxidation during the cell death process are usually present during the ferroptosis process and are iron-dependent. It is a type of regulated necrosis, distinct from apoptosis (which plays a crucial role in the body's normal process of maintaining cellular homeostasis [78]), or necrotosis, and is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Tumor cells that evade other forms of cell death are thought to maintain or acquire sensitivity to ferroptosis. Therefore, the therapeutic development of ferroptosis in cancer has received increasing attention [79; 80]. More and more studies have shown that the relationship between ferroptosis and cancer is very complex, and ferroptosis is expected to become a new cancer treatment method. During ferroptosis, there are distinct changes in mitochondrial morphology [81], including loss of structural integrity, such as smaller-than-normal mitochondria, condensed mitochondrial membrane density, and reduced mitochondrial cristae [82]. The Ras-mitogen-activated protein kinase (MEK) signaling activation can contribute to cancer cells' sensitivity to ferroptosis. This sensitivity can result from its promotion of iron abundance in cancer by controlling both transferrin receptors and ferritin [81]. Also, microRNA and lncRNAs are increasingly recognized as crucial mediators in ferroptosis regulation. The susceptibility of various types of cancers to ferroptosis is significantly different. The p62-Keap1-Nrf2 pathway plays a key role in rescuing HCC cells from ferroptosis. In addition, the Ras/Raf/MEK pathway is indicated to be a critical target for ferroptosis in HCC treatment [83]. A study by [84] demonstrated that the upregulation of MT-1G by the activation of NRF2 contributes to sorafenib resistance in human HCC cells. Moreover, it is not dependent on kinase inhibition, and the upregulation of MT-1G limits sorafenib-induced lipid peroxidation and subsequent ferroptosis. In addition, blocking MT-1G expression enhances the anticancer activity of sorafenib through the induction of ferroptosis in vitro and in vivo [85]. Another study by [PERSON] et al. investigated the underlying GSTZ1 mechanism of sorafenib-induced ferroptosis in HCC. The authors demonstrated that GSTZ1 was significantly reduced in sorafenib-resistant HCC cells. This reduction further enhanced NRF2 pathway activation and augmentation in the glutathione peroxidase 4 (GPX4) level, which, in turn, suppressed sorafenib-induced ferroptosis. In addition, the sorafenib and GPX4 inhibitor (RSL3) combination significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis, which resulted from increased ectopic iron and lipid peroxides. The combination of sorafenib and RSL3 has a synergistic therapeutic effect on HCC progression in Gstz1-/- mice in vivo. All these results demonstrated that GSTZ1 can enhance sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. The authors demonstrated that combination therapy of sorafenib and the GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment [77]. Sorafenib resistance in HCC is often mediated by the activation of alternative survival pathways like PI3K/AKT and compensatory mechanisms that inhibit cell death, including the glutathione (GSH) antioxidant system. Ferroptosis can be exploited by targeting these compensatory pathways, specifically the cystine/glutamate antiporter system Xc--, which plays a key role in regulating intracellular GSH levels. Inhibition of the system Xc-- leads to decreased GSH levels, increased R.O.S., and lipid peroxidation, sensitizing HCC cells to ferroptosis [86]. Research has shown that combining sorafenib with ferroptosis inducers, such as erastin, can significantly enhance sorafenib's therapeutic efficacy by overcoming the resistant tumor cells that escape apoptosis [8; 87]. LncRNAs regulate ferroptosis cell death in several cancers.