# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Primary Resistance
#### 1.2.2 Sestrin 2  
Sestrin 2 is a tumor biomarker that plays a key role in tumor development. Some studies have identified sestrin 2 as a tumor suppressor gene, while others have identified it as an oncogene [45]. Sestrin 2 is an essential part of the sestrin stress-induced protein family and participates in the development of tumors [46; 47]. It regulates multiple downstream pathways, among which MAPK and AKT are closely related to cell proliferation and metabolism. The upregulation of sestrin 2 demonstrates primary resistance to sorafenib in HCC [31]. This resistance, which limits the efficacy of sorafenib, is a significant barrier to successful treatment outcomes in HCC patients. One of the primary mechanisms by which sestrin 2 confers resistance is through the activation of the PI3K/AKT signaling pathway. Sestrin 2 enhances PI3K/AKT signaling in HCC cells, promoting cell survival, proliferation, and metabolism. Upon activation, PI3K facilitates the phosphorylation of AKT, a central kinase that inhibits pro-apoptotic pathways while supporting cellular growth and energy metabolism. The phosphorylation cascade driven by AKTactivation leads to downstream effects such as increased glucose uptake, enhanced lipid biosynthesis, and inhibition of apoptosis, all of which contribute to the resistance of HCC cells to sorafenib [48; 49]. Sestrin 2 mediates this resistance by activating the AKT and AMPK signaling pathways, which are critical for cell survival and metabolism. The upregulation of sestrin 2 in HCC cells enhances the phosphorylation and activation of AKT. This key kinase promotes cell survival by inhibiting apoptosis and supporting metabolic processes essential for cell growth. Sestrin 2 activates AMPK, an energy sensor that helps maintain cellular energy balance under stress conditions induced by sorafenibib. This dual activation of AKT and AMPK by sestrin 2 provides a survival advantage to HCC cells, enabling them to resist the cytotoxic effects of sorafenibib [31; 50]. AMPK activation also inhibits the mTOR1 signaling pathway, which drives protein synthesis and cell proliferation. By inhibiting mTOR1, sestrin 2 creates a feedback mechanism that enables HCC cells to adapt their metabolic demands to environmental stressors, including sorafenibib-induced stress [51]. In addition, the knockdown of sestrin 2 increases sensitivity to sorafenibib, resulting in higher apoptosis rates and reduced proliferation, underscoring the importance of these pathways in sestrin 2-mediated resistance. Sestrin 2 belongs to the family of stress-response or stress-induced proteins; it has been reported to stress in several organs. Sestrin 2 is associated with decreased glomerular parietal epithelial cells [52], decreased/regulated autophagy, and the promotion of human serum albumin (HSA)-induced epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress in HK-2 cells [52; 53]. Sestrin 2 has also been reported to alleviate fibrosis and ER stress in liver-related diseases [54]. The function of sestrin2 has been studied in high glucose-stimulated mesangial cells, where it is downregulated and induces fibrosis through the AMPK pathway [54]. Additionally, sestrin 2 alleviates liver ER stress via the pathway, contributing to increased ER stress and regulating protein synthesis through eEF2 inactivation [55]. lncRNA CDKN2B antisense RNA1 has been shown to be associated with sestrin 2 in a different study [56].