METTL3/m6A‐Dependent SERPINE1/VEGFA Axis Mediates Sublethal Heat‐Induced Angiogenesis in Hepatocellular Carcinoma

Heat ablation techniques, such as microwave and radiofrequency ablation, are established interventions for hepatocellular carcinoma (HCC). However, incomplete ablation often leads to angiogenesis-driven metastasis and recurrence, undermining long-term treatment efficacy. The molecular mechanisms facilitating post-ablation angiogenesis remain poorly understood. In this study, we identified a marked upregulation of SERPINE1 following sublethal heat treatment, which was corroborated in both rabbit models and human HCC cell lines. Further investigation revealed that SERPINE1 promotes angiogenesis, at least in part, through vascular endothelial growth factor A (VEGFA) activation after sublethal heat exposure. We further delineated that METTL3 and IGF2BP1 regulate SERPINE1 expression via an N6-methyladenosine (m6A)-dependent pathway. The proangiogenic role of SERPINE1 was substantiated using patient-derived HCC organoids and in vivo models, where the small-molecule inhibitor PAI-039 significantly attenuated sublethal heat ablation-induced angiogenesis and tumor proliferation. Our findings illuminate the METTL3/IGF2BP1/SERPINE1/VEGFA axis as a novel therapeutic target for improving HCC heat ablation outcomes. Therapeutically, PAI-039 emerges as a potent adjunctive agent that could synergistically enhance the efficacy of thermal ablation in HCC management.