SPTAN1 lactylation accelerates hepatocellular carcinoma progression by promoting NOTCH1-HES1 activation and immunosuppression

SPTAN1 is essential for neuronal function, but its role in cancer is unclear. This study reveals that SPTAN1 undergoes lactylation at K1952 and K1957 in HBV-positive hepatocellular carcinoma. AARS1 mediates this modification, while HDAC1 removes it. HBV infection enhances glycolysis and lactate production, driving SPTAN1-kla, which disrupts cytoplasmic phase separation and promotes nuclear translocation. In the nucleus, SPTAN1-kla activates NOTCH1-HES1 signaling via CBFB, stimulating HCC proliferation, and boosts PGE2 production, leading to CD8+ T-cell exhaustion. Blocking SPTAN1-kla with inhibitory peptides suppresses tumor growth in preclinical models. Thus, SPTAN1-kla acts as an oncogenic driver in HBV-related HCC and represents a potential therapeutic target.

非红细胞血影蛋白α链1（SPTAN1）对神经元功能至关重要，但其在癌症中的作用尚不明晰。本研究发现，在乙型肝炎病毒（HBV）阳性肝细胞癌（hepatocellular carcinoma, HCC）中，SPTAN1会在K1952与K1957位点发生乳酰化修饰。丙氨酰-tRNA合成酶1（AARS1）介导该修饰过程，而组蛋白去乙酰化酶1（HDAC1）则可去除该修饰。HBV感染可增强糖酵解与乳酸生成，进而诱导SPTAN1发生乳酰化修饰（SPTAN1-kla），该修饰会破坏细胞质相分离并促进其向细胞核转位。在细胞核内，SPTAN1-kla可通过核心结合因子β亚基（CBFB）激活NOTCH1-HES1信号通路，进而刺激肝细胞癌增殖；同时还能促进前列腺素E2（PGE2）的生成，最终导致CD8+ T细胞耗竭。使用抑制性肽阻断SPTAN1-kla，可在临床前模型中抑制肿瘤生长。综上，SPTAN1-kla是HBV相关肝细胞癌的致癌驱动因子，同时也是一种潜在的治疗靶点。