Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.

肝细胞癌（HCC）是一种典型的致命恶性肿瘤，表现出遗传异质性和有限的治疗反应。我们在此证明，HCC 持续抑制尿素循环基因表达，从而成为外源精氨酸营养缺陷型。令人惊讶的是，精氨酸的输入唯一依赖于阳离子氨基酸转运蛋白 SLC7A1，其抑制作用可减缓体外和体内肝癌细胞的生长。此外，精氨酸剥夺会引发综合应激反应，促进 HCC 细胞周期停滞和静止，这依赖于一般控制非阻抑性 2 (GCN2) 激酶。抑制精氨酸剥夺的 HCC 细胞中的 GCN2 相反会促进衰老表型，使这些细胞容易受到衰老化合物的影响。临床前模型证实，饮食精氨酸剥夺、GCN2 抑制和衰老疗法相结合可促进 HCC 细胞凋亡和肿瘤消退。这些数据表明通过靶向 SLC7A1 和/或精氨酸限制、GCN2 抑制和抗衰老药物的组合来治疗人类肝癌的新策略。