MiR-22/GLUT1 Axis Induces Metabolic Reprogramming and Sorafenib Resistance in Hepatocellular Carcinoma

Immunotherapy approval has revolutionized the management of hepatocellular carcinoma (HCC) patients. Sorafenib remains a first-line therapeutic option for those patients who are ineligible for immunotherapy, but the onset of resistance compromises treatment efficacy, making the need for biomarkers more urgent. This study aims to investigate the role of miR-22 in metabolic reprogramming and as a possible candidate in HCC. QPCR analysis of miR-22 was performed in HCC patients and preclinical models. GLUT1 targeting by miR-22 was investigated in HCC cells by functional analysis. MiR-22/GLUT1 axis involvement in metabolic changes, tumor aggressiveness, and sorafenib response was evaluated by cellular and metabolic assays. Circulating miR-22 was analyzed in sorafenib-treated HCC patients and rats. MiR-22 is downregulated in HCCs and associates with aggressive tumor features. MiR-22 modulates HIF1A pathway and survival in stressful conditions. It induces glycolytic shift and enhances cancer cell plasticity and sorafenib resistance by GLUT1 targeting. High miR-22 serum levels associate with sorafenib resistance in HCC patients and rats. GLUT1 inhibition in low miR-22-expressing HCC cells ameliorates sorafenib efficacy. MiR-22 deserves attention as a predictive biomarker of sorafenib response. GLUT1 inhibition could be exploited in combination with sorafenib in HCC patients with high circulating miR-22 levels.