The Impact of TIGAR on Prognosis in Hepatocellular Carcinoma; Association with Tumor Microenvironment and Ferroptosis

<b><i>Introduction:</i></b> <i>TP53</i>-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited. <b><i>Methods:</i></b> A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro. <b><i>Results:</i></b> Patients were divided into TIGAR-positive (<i>n</i> = 80, 20.7%) and -negative (<i>n</i> = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ <i>des</i>-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (<i>p</i> &lt; 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (<i>p</i> = 0.0450), larger number of CD68-positive macrophages (<i>p</i> = 0.0058), larger number of programmed death-ligand 1-positive cases (<i>p</i> = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (<i>p</i> = 0.0004). In vitro, <i>TIGAR</i> knockdown decreased cell motility and induced ferroptosis. <i>TIGAR</i> knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by <i>TIGAR</i> knockdown was inhibited by liproxstatin and baicalein treatment. The combination of <i>TIGAR</i> knockdown and lenvatinib further induced ferroptosis. <b><i>Conclusion:</i></b> High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.