Advances in the mechanism of small extracellular vesicles promoting the development of hepatocellular carcinoma through multi-network fusion

Xiaoying Yuan¹Defa Huang²Liang Peng³Lijuan Wang⁴Yilong Lin⁴Jiawei Yan⁴Youming Qiu⁵Chenggui Song⁵Qi Wang^5*

• ¹The First School of Clinical Medicine,Gannan Medical University, Ganzhou, China
• ²Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
• ³Department of Research and Education, The Second People's Hospital of Jingdezhen, Jingdezhen, China
• ⁴School of Medical Technology, Gannan Medical University, Ganzhou, China
• ⁵The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China

Hepatocellular carcinoma (HCC) is a highly malignant epithelial tumor characterized by global high incidence and poor clinical prognosis. Radical surgical resection, as the standard treatment for early-stage HCC patients, has been extensively validated for its therapeutic efficacy. However, epidemiological studies indicate that most patients are already in advanced stages at initial diagnosis, losing eligibility for radical treatment. Notably, HCC pathogenesis exhibits marked etiological heterogeneity, posing significant challenges for clinical management. Although significant breakthroughs have been made in understanding HCC drivers at pathophysiological levels, translational applications of these findings remain hindered by multiple barriers. Currently, elucidating the molecular mechanisms of HCC pathogenesis and identifying effective therapeutic targets constitute major research priorities in this field.Small extracellular vesicles (sEVs) are phospholipid bilayer vesicles (30-150nm in diameter) carrying functional proteomes and nucleic acids (e.g., miRNAs, lncRNAs) with substantial biological activity. Studies demonstrate that sEVs contribute to malignant phenotype acquisition by modulating key signaling pathways such as PI3K/AKT and Wnt/ β -catenin. These molecular cascades ultimately confer hallmark pathological features including aberrant proliferation, apoptosis resistance, and immune evasion to tumor cells. Within multi-network regulatory systems, sEVs serve as crucial intercellular messengers mediating tumor cell interactions with other tumor microenvironment (TME) components (e.g., cancer-associated fibroblasts, immune cells). Such communication facilitates TME reprogramming, pro-angiogenic phenotypic shifts, and therapy resistance development. Nevertheless, the precise molecular mechanisms of sEVs in HCC pathogenesis remain incompletely understood, warranting further exploration of their translational potential in clinical practice.