# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
## 3 Conclusions and Future Directions
#### Relevance of sorafenib Resistance in HCC  
Sorafenib has long been a mainstay in the treatment of advanced HCC. However, the development of resistance to sorafenib presents a significant hurdle in effectively managing this aggressive cancer. Understanding the mechanisms behind sorafenib resistance is crucial for devising more effective therapeutic strategies and improving patient outcomes. Research into sorafenib resistance in HCC has uncovered several key mechanisms. One major pathway involves the activation of alternative signaling pathways that circumvent sorafenib's inhibitory effects on the RAF/MEK/ERK pathway. For example, upregulation of the PI3K/AKT/mTOR pathway has been identified as a driver of sorafenib resistance, promoting tumor cell survival and proliferation despite treatment [141; 142]. Furthermore, resistance can arise due to dysregulated angiogenesis, a process vital for cancer progression. Increased expression of pro-angiogenic factors such as VEGF and bFGF can lead to enhanced tumor vascularization, thereby reducing the efficacy of sorafenib's anti-angiogenic effects [143; 144]. The tumor microenvironment also plays a critical role in mediating sorafenib resistance. Stromal cells like cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) secrete cytokines and growth factors that promote tumor growth and resistance to sorafenib Gib [50; 145]. Moreover, genetic mutations and epigenetic modifications contribute to sorafenib resistance by altering drug metabolism, apoptosis, and DNA repair mechanisms. Mutations in genes encoding drug transporters or metabolizing enzymes can affect sorafenib uptake and metabolism, while epigenetic changes can modulate gene expression involved in drug sensitivity. Overcoming sorafenib resistance necessitates the development of innovative therapeutic approaches. Combination therapies, such as targeting multiple signaling pathways simultaneously or combining anti-angiogenic agents with immunotherapy, show promise in preclinical and clinical studies [146]. LncRNA-targeted therapies hold great potential as novel approaches for overcoming sorafenib resistance. Based on current studies, lncRNAs could serve as biomarkers for diagnosis and prognosis and as therapeutic targets to modulate resistance pathways. Specifically, lncRNA silencing or inhibition strategies, such as antisense oligonucleotides or CRISPR-Cas9-based gene editing, show promise in preclinical models. Targeting key lncRNAs involved in regulating PI3K/AKT/mTOR, AMPK, and ABC transporter pathways could enhance sorafenib's efficacy in resistant HCC. Future directions in studying sorafenib resistance involve advancing our understanding of the complex mechanisms underlying resistance and developing novel strategies to overcome them. To summarize, the key areas for further investigation include the identification of biomarkers using genomic and proteomic profiling, utilizing sequencing technologies, and liquid biopsies exploring the circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). Other key areas include mechanistic studies, including single-cell analysis and microenvironment interactions; targeted therapies and combinatorial approaches, including alternate pathway inhibition and immunotherapy combinations; epigenetic regulation, primarily epigenetic modifications in regulating sorafenib sensitivity and resistance; and drug delivery and pharmacokinetic approaches, including nanomedicine approaches and pharmacokinetic studies. Finally, this can be achieved through patient stratification and personalized medicine, including predictive models and clinical trial design. In summary, sorafenib's resistance poses a significant challenge in treating advanced HCC. Understanding the diverse mechanisms of driving resistance is essential for devising effective treatment strategies to improve patient outcomes in this lethal disease.