# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
## 3 Conclusions and Future Directions  
This study highlights several lncRNAs that play pivotal roles in HCC progression and sorafenib resistance. Notable examples include HULC, MALAT1, H19, NR2F1-AS1, and FOXD2-AS1, each of which contributes to chemoresistance through different molecular mechanisms, such as regulating drug efflux transporters (e.g., ABC transporters) or modulating apoptosis and autophagy pathways. Additionally, lncRNAs like NEAT1, SNHG1, and UBE2 CP3 are implicated in controlling angiogenesis and metabolic adaptations, further underscoring their involvement in sorafenib resistance. Sorafenib is the first-line treatment targeted drug for patients with renal cell carcinoma (RCC) as a tyrosine kinase inhibitor. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Cancer Type** & **Resistance Type** & **Mechanism** & **References** \\ \hline HCC & Primary & Altered drug metabolism (CYP450 enzymes) & [136] \\ \hline HCC & Primary & Upregulation of drug efflux pumps (MDR1, ABCB1) & [122] \\ \hline HCC & Primary & Activation of AKT/mTOR pathway & [137] \\ \hline HCC & Secondary & Epithelial to mesenchymal transition (EMT) & [44] \\ \hline RCC & Primary & Inactivation of pro-apoptotic signals (p53 mutations) & [138] \\ \hline RCC & Primary & Activation of alternate survival pathways (VEGF, mTOR) & [87] \\ \hline RCC & Secondary & Tumor microenvironment modifications (hypoxia) & [139] \\ \hline RCC & Secondary & Enhanced DNA repair mechanisms (BRCA1, BRCA2) & [140] \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Mechanisms of Primary and Secondary Resistance in HCC and RCC. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Long** & **Effects on** & & \\
**Noncoding** & **Sorafenib** & **Target** & **Mechanisms Mediating Resistance/Major** \\
**RNAs** & **Resistance** & & **Effects** \\ \hline  & & miR-495-3p, SATB1, & & LUCAT1 significantly inhibits RCC cell \\  & & cyclin D1, CDK4, & proliferation, migration, and invasion, and can & \\  & & p-Rb, AKT & lead to the accumulation of renal cancer cell lines & \\ \hline  & & miR-34/miR-R49 & & ARSR promotes resistance in RCC and may also & \\  & & and AXL/c-Met & be packaged into exosomes to transfer drug & [42] \\  & & axis & resistance & \\ \hline  & & miR-378a- & & \\  & & & 5p/DAB2 IP axis & Promotes angiogenesis & [42; 131] \\ \hline GAS5 & Inhibiting & miR-21/SOX5 axis & Inhibit sorafenib resistance & \\ \hline  & & & Promotes proliferative and invasive features, as & \\  & & & well as sorafenib resistance in RCCcells by & \\  & & & & regulating C-X-C motif chemokine receptors 5 & \\  & & & (CXCR5) by acting as a sponge for miR-653 & \\ \hline SARCC & Inhibiting & AR & Targeted therapy inhibiting invasion, migration, & \\  & & & and proliferation in RCC & [132] \\ \hline  & & & SRLR directly interacts with nuclear transcription & \\  & & & factor NF-\(\kappa\)B and binds to and enhances IL-6 & \\  & & & transcription, activating STAT3 and promoting & \\  & & & sorafenib resistance & \\ \hline  & & & SNHG12 has been described as a critical molecule & \\  & & & mediating tumor development in various tumors, & \\  & & & including RCC & \\ \hline  & & & KIF9-AS1 & KIF9-AS1 sponges miR-497–5p to activate TGF-\(\beta\) & \\  & & & and autophagy signaling pathways, promoting & \\  & & & RCC cell resistance to sorafenib & \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Studies identifying the lncRNAs target, mechanism in RCC. Hence, kidneys are the nearest organ of the liver, and due to severe forms of liver disease or HCC, kidneys are also affected/damaged. Therefore, in this study, we have presented a precise message about sorafenib resistance, which is extremely common in HCC and RCC therapy, and we have shown the molecular mechanisms of sorafenib in HCC and RCC progression. The development of sorafenib resistance in HCC and RCC cells in vitro is essential for exploring the acquired sorafenib mechanics.