IGF2BP1/AIFM2 axis regulates ferroptosis and glycolysis to drive hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is aggressive liver tumor that is the third leading cause of cancer death. Ferroptosis and glycolysis play key roles in HCC progression. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) in involved in regulating ferroptosis and glycolysis in cancers, but its role in HCC remains unclear. This research explored the function of AIFM2 in HCC.

AIFM2 expression in HCC tissues was evaluated using the UALCAN and GEPIA databases, as well as RT-qPCR. Kaplan-Meier survival analysis analyzed the correlation between AIFM2 and the prognosis of HCC patients. EdU and transwell assays were utilized to examine HCC cell proliferation, migration, and invasion. Ferroptosis markers were analyzed by measuring iron levels, ROS production (DCFH-DA assay), and oxidative stress indicators (SOD, MDA, and GSH). Glycolytic activity was assessed through glucose uptake, lactate production, and ATP levels. m6A modification on AIFM2 mRNA was confirmed by MeRIP assay, and mRNA stability was evaluated with Actinomycin D treatment. Tumor growth and metastasis were studied in xenograft and lung metastasis models.

UALCAN analysis showed that AIFM2 was significantly upregulated in HCC tissues, which correlated with poor survival rates of HCC patients. IGF2BP1 was also highly expressed in HCC tissues and positively correlated with AIFM2 levels in HCC tissues. Functionally, AIFM2 knockdown suppressed glycolysis and enhanced ferroptosis, while its overexpression had opposite effects. IGF2BP1 was found to stabilize AIFM2 mRNA via m6A modification, promoting AIFM2 expression. IGF2BP1 knockdown reduced glycolysis, proliferation, and invasion while promoting ferroptosis, while AIFM2 overexpression could reverse this effect. In vivo, IGF2BP1 or AIFM2 silencing significantly suppressed tumor growth and metastasis.

IGF2BP1 stabilized AIFM2 mRNA to regulate ferroptosis and glycolysis and promoted HCC progression.