The identification of genes related to METTL14 inhibition in radiation- induced hepatocyte death based on bioinformatics analysis

Background: Radiation-Induced Liver Disease (RILD) is a major dose-limiting complication in radiotherapy for hepatocellular carcinoma, yet its molecular mechanisms remain incompletely understood compared to radiation injury in other organs. Programmed cell death (PCD) pathways like apoptosis, pyroptosis, and ferroptosis are crucial in RILD development. The m6A modification enzyme METTL14 is implicated in driving these PCD pathways, but its role in radiation-induced hepatocyte injury was unknown. This study aimed to elucidate METTL14's function and molecular mechanisms in RILD pathogenesis to identify novel therapeutic targets. Methods: C57BL/6J mice received 30 Gy liver irradiation (5 Gy × 6 fractions). METTL14 overexpression was achieved by tail-vein injection of AAV-METTL14. Liver injury was evaluated by transmission electron microscopy (TEM), RNA-seq, bioinformatics and molecular validation (qRT-PCR / Western blot). Results: Irradiation markedly reduced hepatic METTL14 protein. Overexpression of METTL14 preserved hepatocyte ultrastructure and decreased cell death. Transcriptomic profiling revealed 964 differentially expressed genes (DEGs), were apoptosis-related. Functional enrichment and PPI network analyses identified ten hub genes, with HMOX1 and SERPINE1 exhibiting the most consistent up-regulation at both mRNA and protein levels. A TF–mRNA–miRNA regulatory network further implicated hsa-miR-145-5p and 33 upstream transcription factors in controlling these hubs. Conclusion: METTL14 overexpression protects against radiation-induced hepatocyte injury primarily through modulation of apoptosis and ferroptosis pathways, with HMOX1 and SERPINE1 serving as key downstream effectors. Targeting the METTL14–SERPINE1- miR-145-5p axis may offer a novel therapeutic strategy for RILD.