# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
###### Abstract  
Hepatocellular carcinoma (HCC), a liver cancer originating from hepatocytes, is a major health concern and among the most common malignancies worldwide. Soraenib, approved by the U.S. F.D.A., is the primary first-line treatment for patients with advanced HCC. While the preferred first-line systemic regimen for HCC is immunotherapy with Atezolizumab plus bevacizumab or Tremelimumab-acctl + durvalumab, Sorafenib is still an alternative recommended regimen. While some patients with advanced HCC may benefit from Sorafenib treatment, most eventually develop resistance, leading to poor prognosis. Long noncoding RNAs (lncRNAs) have been found to play a critical role in tumorigenesis and the development of HCC, as well as other cancers. They are also key players in tumor drug resistance, though the mechanisms of lncRNAs in Sorafenib resistance in HCC remain poorly understood. This review summarizes the molecular mechanisms contributing to Sorafenib resistance in HCC with their potential correlation with lncRNAs, including the roles of transporters, receptors, cell death regulation, and other influencing factors. long noncoding RNA (lncRNA); Sorafenib resistance; hepatocellular carcinoma (HCC); EGFR; autophagy; VEGFA; proteomics; renal cell carcinoma (RCC) 2024163904.163904.  
directly affects the safety of the treatment and plays a significant role in determining the prognosis of HCC [1; 2]. Sorafenib was approved in 2007 for the treatment of advanced HCC, a milestone in the history of HCC treatment. Sorafenib is a preferred treatment for advanced hepatocellular carcinoma (HCC) [3]. This drug has demonstrated the benefit of survival over supportive care in advanced HCC. In the Sorafenib Hepatocellular Carcinoma Evaluation Randomized Protocol (SHARP) trial, 5.5 months (median time to progression) and 10.7 months (survival) were observed in sorafenib-treated patients, compared to a placebo. The absolute improvement in survival was 2.8 months [4; 5; 6]. Various studies have shown that patients treated with sorafenib have an increased median survival time [7] and an increased resistance level, significantly limiting the efficiency of sorafenib therapy [8]. This is the primary factor causing hindrances in its clinical application. Long noncoding RNAs (LncRNAs) are non-protein-coding ribonucleic acids (RNAs) with more than 200 nucleotides. LncRNAs have been found to play critical roles in developing various cancers, including HCC [9; 10]. Although the role of lncRNAs in disease onset has received attention, studies on the relationship between lncRNAs and chemotherapy resistance, especially in sorafenib-resistant HCC, are scarce. The role of lncRNAs in the pathogenesis and progression of various cancers, including hepatocellular carcinoma (HCC), is crucial. These lncRNAs regulate vital processes such as proliferation, migration, apoptosis, autophagy, the cell cycle, tumorigenesis, and metastasis in HCC and related cancers such as renal cell carcinoma (RCC) [11]. Additionally, because the kidney is located near the liver and often plays a compensatory role in liver disease, RCC is also significantly impacted. We will include relevant information on RCC, particularly in the context of sorafenib resistance. A small percentage of patients can get an advantage from sorafenib, and the same proportion of patients commonly acquire drug resistance within a small amount of time [12]. Patients administered with sorafenib usually experience side effects such as gastrointestinal, physical, or skin-related issues (e.g., skin reactions, weight loss, and/or diarrhea) [13; 14]. When the effects are severe, sorafenib can cause high blood pressure and/or abdominal pain, which can lead to this drug's discontinuation [6; 15; 16]. The mechanisms of sorafenib resistance should be well established. The role of epigigenetics, transport processes, regulated cell death, and the tumor microenvironment in the sorafenib resistance in HCC and RCC have been established based on recent studies [17; 18; 19].