In regions like North America and Europe, there has been an uptick in both mortality and morbidity rates associated with HCC. This contrasts with areas like Japan and China, where HCC was once prevalent and these regions were deemed high-risk, but now are experiencing a decline in both mortality and morbidity rates. As with other cancer types, HCC development cannot be attributed to a single cause. Instead, it results from a combination of factors, including chronic infections with HBV and HCV, alcohol consumption, diabetes mellitus, and NAFLD (Kulik and El-Serag, 2019, Singal and El-Serag, 2015, Zongyi and Xiaowu, 2020). In the USA, HCC has exhibited the most significant rise in cancer-related fatalities, signaling a trend that government authorities need to be alerted to. For example, a study conducted across all 50 states in the US revealed a marked escalation in the incidence rate of HCC from 2000 to 2009, with an annual average growth rate of 4.5% (White et al., 2017). HCC is identified as the liver's most severe tumor form (Huang et al., 2020a). Typically, at the point of diagnosis, HCC patients present with multiple nodules, a condition often resulting from synchronous tumor growth or spread within the liver tissue. HCC cells are notably prone to proliferating in blood vessels, with a potential to invade the portal or hepatic veins (Sangro et al., 2021, Llovet et al., 2016). AFP serves as a widely used biomarker for the early detection of HCC, offering prognostic insights and aiding in gauging the therapy response. The selection of therapeutic interventions for HCC varies regionally (Hepatology, 2018, Heimbach et al., 2018, Vogel et al., 2018, Omata et al., 2017). For HCC cases without detectable tumor spread beyond the liver, locoregional treatments are considered effective. Treatment options such as liver transplantation, resection, percutaneous ablation, TACE, and radioembolization are selected based on tumor size, location, and patient comorbidities (Hepatology, 2018). Given the resistance of HCC cells to cytotoxic chemotherapy, systemic therapy emerges as a viable alternative. A significant finding in 2008 revealed that oral administration of sorafenib, a multi-tyrosine kinase inhibitor, significantly enhances survival and prognosis in patients with advanced-stage HCC (Llovet et al., 2008). However, the combined utilization of TKI and TCE in the intermediate stage of HCC did not demonstrate similar therapeutic efficacy (Lencioni et al., 2016, Kudo et al., 2014).

The development of HCC is mediated via different mechanisms, such as the inhibition of tumor-suppressor factors like p53, activation of oncogenic items including K-ras, and the abnormal level of molecular pathways like MAPK, phosphoinositide 3-kinase (PI3K), JAK/signal transducer and activator of transcription (STAT), nuclear factor-kappaB (NF-κB), and Wnt/β-catenin. Additionally, exosomes exert a significant function in mediating cell-to-cell communication in this context (Jiang et al., 2019, Aravalli et al., 2013). The m6a modification of circRNA HPS5 results in the upregulation of the HMGA2, which promotes HCC progression (Rong et al., 2021). Activated fibroblasts can secrete FSTL1, stimulating the Akt/mTOR/eIF4E-binding protein 1 (4EBP1) axis, thereby enhancing invasion and stemness of HCC (Loh et al., 2021). Overexpression of circMRPS35 increases syntaxin 3 (STX3) expression through miR-148a sponging, contributing to cisplatin resistance in HCC (Li et al., 2022a). The role of proline-rich coiled-coil 2 A (PRRC2A) in HCC is notable for its regulation of immune infiltration; overexpression of PRRC2A leads to a lower response of tumor cells to immunotherapy and can serve as a biomarker (Liu et al., 2021a). REXO4 is associated with increased progression and altered lipid metabolism in HCC, correlating with poor prognosis (Ruan et al., 2021). Furthermore, the induction of glycolysis in HCC, which can enhance tumor proliferation, is mediated by LNCAROD through the overexpression of pyruvate kinase M2 (PKM2) (Xu et al., 2021a).