METTL3/IGF2BP1/SERPINE1/VEGFA pathway contributes to sublethal heat ablation-induced pro-angiogenesis in HCC

Sublethal heat ablation is a well established strategy to treat hepatocellular carcinoma (HCC). However, the incomplete ablation induced angiogenesis and subsequent metastasis and recurrence is the major problem that results in the failure of HCC treatment. Unfortunately, the underlying mechanism by which ablation triggered angiogenesis remains to be investigated. Here we found that SERPINE1 expression was robustly stimulated in our sublethal heat treatment model, which was further confirmed in rabbit model and human HCC cell lines.Further exploration illustrated that SERPINE1 facilitated the angiogenesis partially via VEGFA after sublethal heat treatment. Importantly, both HCC patient derived organoids and animal model further demonstrated the proangiogenic function of SERPINE1, and targeting SERPINE1 by the small molecular inhibitor PAI039 dramatically abrogated the sublethal heat ablation induced angiogenesis and tumor growth in vivo.Therapeutically , the small molecule PAI039 is a promising drug candidate that can be used in combination with heat ablation for HCC treatment.