癌症仍是严重威胁人类健康的疾病，其中原发性肝癌的严重程度较高。在原发性肝癌中最主要的类型是肝细胞癌（Hepatocellular caicinoma，HCC），占原发性肝癌病例的 80%左右。浸润型 HCC 由于其侵袭程度高等因素，治疗和预后都面临着较大的挑战。研究发现，癌症与神经会通过相互作用在肿瘤的进展中发挥作用。癌细胞会分泌神经营养因子，促进神经进入肿瘤微环境（tumor microenvironment，TME），这一过程称为新神经生成。此外，神经系统通过分泌一系列趋化因子和神经递质，对刺激癌细胞生长、增殖、血管生成和侵袭具有重要影响。自主神经被证明在肿瘤微环境中参与癌症的生长和转移，因此调控肿瘤组织中局部神经对癌症有着治疗效果。神经递质是肿瘤微环境中重要的组成部分，目前研究发现的神经递质影响肿瘤细胞都是通过结合特定的神经递质受体，激活肿瘤细胞，影响肿瘤细胞的多种生物学行为来实现的。 γ-氨基丁酸（gamma-aminobutyric acid，GABA）是人 CNS 中的一种主要抑制性神经递质，被认为与某些类型的癌症发展有关。目前已知的 GABA 影响肿瘤发生的方式，主要是通过结合肿瘤细胞表面的受体激活信号通路。在大多数情况下，GABA 通过 GABAA 受体途径刺激肿瘤细胞增殖，通过 GABAB 受体抑制肿瘤细胞生长。然而，GABA 作为一种内源性物质，是否能像其他代谢物一样，能够通过其他方式进入肿瘤细胞中并与代谢物感受器结合从而发挥作用，这仍不清楚。此外，GABA 在肝细胞癌中的新合成方式及其发挥作用的方式尚未被研究。 首先，本研究在队列分析、小鼠实验中发现 GABA 对于 HCC 转移有促进作用，而对于原发部位的肿瘤生长并无明显作用。其次，通过人类 HCC 数据库分析和细胞迁移侵袭实验，鉴定出醛脱氢酶 9 家族成员 A1（ALDH9A1 aldehyde dehydrogenase 9 family member A1，ALDH9A1），而不是谷氨酸脱羧酶 1（glutamate decarboxylase 1，GAD1），是人类 HCC 中产生 GABA 的主要合成酶。本研究发现，ALDH9A1 在 HCC 的肺转移部位上调，其缺失会导致 HCC 转移受损。接下来，探究了 GABA 促进 HCC 转移的机制。对 GABA 处理的 Huh7 细胞的 RNA seq 数据进行差异基因分析结合质谱数据，筛选出 GABA 的处理会激活 Wnt/beta-catenin 信号通路。进一步研究发现，GABA 直接结合并阻止 beta-catenin 磷酸化，从而减少其泛素化，稳定 beta-catenin，导致 Wnt/beta-catenin 信号的激活，从而增强HCC 转移。因此，本研究发现 GABA 有助于 HCC 转移，ALDH9A1 是 HCC 中的主要GABA合成酶，并揭示了beta-catenin与Wnt/beta-catenin信号通路在感知GABA中的作用。本研究报道了肿瘤细胞感知神经递质的一种新方式，鉴定出神经递质在肿瘤细胞内的代谢感受器，不仅发现了肿瘤细胞的新代谢机制，而且为肿瘤治疗提供了新的想法和靶点。

Cancer remains a disease that seriously affects human health, among which the severity of primary liver cancer is relatively high. Hepatocellular carcinoma (HCC) is the predominant type among primary liver cancers, accounting for approximately 80% of primary liver cancer cases. Invasive HCC, due to its highly aggressive nature and other qualities, presents substantial challenges in terms of treatment and prognosis. Recent studies have revealed that the interaction between cancer and the nervous system plays a crucial part in cancer progression. Cancer cells can secrete neurotrophic factors to promote nerve infiltration into the tumor microenvironment (TME), which is a process known as neoneurogenesis. Furthermore, the nervous system influences cancer growth, proliferation, angiogenesis, and invasion through the secretion of a series of chemokines and neurotransmitters. The autonomic nervous system has been proven to be involved in cancer growth and metastasis within the TME, so manipulating local neural activity in tumors has emerged as a potential therapeutic approach. Neurotransmitters are critical components of the TME. To date, studies have shown that neurotransmitters affect tumor cells primarily through binding to specific neurotransmitter receptors, thereby activating tumor cells and influencing various biological behaviors. One such neurotransmitter, γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the human central nervous system, is believed to be associated with the development of certain cancer types. GABA is known to influence tumorigenesis primarily by binding to surface receptors on tumor cells and activating signaling pathways. In most cases, GABA stimulates tumor cell proliferation via GABAA receptors, while it inhibits tumor growth through GABAB receptors. However, it remains unclear whether GABA, as an endogenous molecule, can enter tumor cells through mechanisms other than its known receptors, possibly by acting as a metabolite sensed by intracellular sensors. In addition, the pathway of de novo GABA synthesis and its functional mechanism in HCC remain poorly understood. In this study, cohort analysis and mouse experiments demonstrated that GABA promotes HCC metastasis, without significantly affecting primary tumor growth. Further analysis of human HCC databases, along with knockdown experiments of ALDH9A1 and GAD1, revealed that ALDH9A1, not glutamate decarboxylase 1 (GAD1), is the primary enzyme responsible for GABA synthesis in human HCC. ALDH9A1 was found to be upregulated in lung metastatic lesions of HCC, and depletion of it impaired metastatic potential. Mechanistically, RNA-seq analysis of GABA-treated Huh7 cells, combined with mass spectrometry, showed that GABA activates the Wnt signaling pathway. Further experiments demonstrated that GABA directly binds to β-catenin, inhibiting its phosphorylation and reducing its ubiquitination, thereby stabilizing β-catenin protein and leading to Wnt/β-catenin pathway activation. This, in turn, promotes HCC metastasis. In conclusion, this study establishes GABA as a promoter of HCC metastasis, identifies ALDH9A1 as the key enzyme in HCC to synthesis GABA, and uncovers a novel role for β-catenin in sensing GABA and mediating Wnt signaling activation. This work reports a new mode by which tumor cells sense neurotransmitters, identifying intracellular metabolic sensors for neurotransmitters, thereby revealing a new metabolic mechanism in cancer cells and providing potential new targets for cancer therapy.