As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.

作为产生 2-AG 和游离脂肪酸的重要水解酶，二酰甘油脂肪酶 α (DAGLA) 参与加剧恶性表型和癌症进展，但 DAGLA/2-AG 轴在 HCC 进展中的作用仍不清楚。在这里，我们发现 HCC 样本中 DAGLA/2-AG 轴成分的上调与肿瘤分期和患者预后相关。体外和体内实验表明，DAGLA/2-AG轴通过调节细胞增殖、侵袭和转移来促进HCC进展。从机制上讲，DAGLA/2AG轴显着抑制LATS1和YAP磷酸化，促进YAP核转位和活性，最终导致TEAD2上调和PHLDA2表达增加，这可以通过DAGLA/2AG诱导的PI3K/AKT通路激活来增强。更重要的是，DAGLA 在 HCC 治疗过程中诱导了乐伐替尼治疗的耐药性。我们的研究表明，抑制 DAGLA/2-AG 轴可能是抑制 HCC 进展并增强 TKI 治疗效果的新治疗策略，值得进一步的临床研究。