Anti-angiogenic therapy is a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but drug resistance remains a major obstacle to its long-term efficacy. Our previous study found that apolipoprotein A2 (ApoA2) was highly expressed in anti-angiogenic drug-resistant HCC. However, the mechanism underlying ApoA2-mediated resistance to anti-angiogenic therapy remains unclear. Here, ApoA2 overexpression markedly promoted HCC cell proliferation, inhibited lenvatinib-induced apoptosis in vitro, and enhanced tumor progression as well as intrahepatic and lung metastasis in vivo. Mechanistically, conditioned medium from ApoA2-overexpressing cells facilitated HUVEC migration and tube formation. Tumors with ApoA2 overexpression showed significantly increased CD31 expression and microvessel density. ApoA2 upregulated HMGB1 expression and activated the IL-17A signaling pathway. Glycyrrhizic acid (Gly) and secukinumab (mab), specific inhibitors of HMGB1 and IL-17A, respectively, synergized with lenvatinib in vivo in subcutaneous xenograft models and reversed ApoA2-driven angiogenesis. Clinically, high ApoA2 expression was strongly correlated with elevated IL-17A expression and poor prognosis. Our findings provided a mechanistic explanation for the failure of anti-angiogenic therapy and suggested a potential therapeutic strategy to overcome ApoA2-mediated resistance in HCC.
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