Li Wenxuan, Zhang Jinghao, Gao Yueqiu, Kong Xiaoni, Sun Xuehua
Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
Biochim Biophys Acta Rev Cancer. 2025 Jul;1880(3):189345. doi: 10.1016/j.bbcan.2025.189345. Epub 2025 May 10.
Hepatocellular carcinoma (HCC) is a highly heterogeneous and complex cancer influenced by both the tumor microenvironment and multi-level regulation of the nervous system. Increasing evidence highlights critical roles of the central nervous system (CNS) and peripheral nervous system (PNS) in modulating HCC progression. Psychological stress and emotional disturbances, representing CNS dysregulation, directly accelerate tumor growth, metastasis, and impair anti-tumor immunity in HCC. PNS involvement, particularly autonomic innervation, extensively reshapes the hepatic tumor microenvironment. Specifically, sympathetic activation promotes immune suppression, tumor cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stemness via β-adrenergic signaling and hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, whereas parasympathetic signals generally exert anti-inflammatory and tumor-suppressive effects mediated by acetylcholine. Neurotransmitters including epinephrine, norepinephrine, dopamine, serotonin, and acetylcholine precisely regulate critical pathways such as AKT/mTOR, ERK, and NF-κB, thereby driving malignant cell behaviors, immune evasion, and chemoresistance. Neuro-targeted pharmacological interventions (e.g., SSRIs, β-blockers, dopamine antagonists) and behavioral therapies have shown efficacy in preclinical studies, underscoring their therapeutic potential. Additionally, neural-associated biomarkers like NEDD9, CNTN1, and nerve growth factor (NGF) exhibit prognostic significance, supporting their future clinical application. By systematically integrating neuroscience with oncology, this review identifies innovative neural-based therapeutic strategies, highlights key mechanistic insights, and outlines promising directions for future research and personalized clinical management of HCC.
肝细胞癌（HCC）是一种高度异质性和复杂性的癌症，受肿瘤微环境和神经系统多级调控的影响。越来越多的证据表明，中枢神经系统（CNS）和外周神经系统（PNS）在调节HCC进展中起着关键作用。心理压力和情绪障碍代表CNS失调，直接加速HCC的肿瘤生长、转移并损害抗肿瘤免疫力。PNS的参与，尤其是自主神经支配，广泛重塑肝脏肿瘤微环境。具体而言，交感神经激活通过β-肾上腺素能信号和缺氧诱导因子1-α（HIF-1α）稳定促进免疫抑制、肿瘤细胞增殖、上皮-间质转化（EMT）和癌症干性，而副交感神经信号通常通过乙酰胆碱介导发挥抗炎和肿瘤抑制作用。包括肾上腺素、去甲肾上腺素、多巴胺、血清素和乙酰胆碱在内的神经递质精确调节关键通路，如AKT/mTOR、ERK和NF-κB，从而驱动恶性细胞行为、免疫逃逸和化疗耐药性。神经靶向药物干预（如选择性5-羟色胺再摄取抑制剂、β受体阻滞剂、多巴胺拮抗剂）和行为疗法在临床前研究中已显示出疗效，强调了它们的治疗潜力。此外，像NEDD9、接触蛋白1（CNTN1）和神经生长因子（NGF）等与神经相关的生物标志物具有预后意义，支持它们未来的临床应用。通过系统地将神经科学与肿瘤学相结合，本综述确定了基于神经的创新治疗策略，突出了关键的机制见解，并概述了HCC未来研究和个性化临床管理的有前景的方向。
