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.