Zengbin Wang, Dongjie Ye, Linqing Wu, Jiayu Liu, Banglun Pan, Zhu Zhang, Xiaoxia Zhang, Yuxin Yao, Nanhong Tang
Nonerythrocytic alphaII-spectrin (SPTAN1) is crucial for neuronal functions, yet its role in oncogenic processes remains inadequately characterized. This study investigates the lactylation (kla) modification of SPTAN1 (SPTAN1-kla) and its mechanistic contributions to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Results indicate that SPTAN1 undergoes lactylation at lysine residues K1952 and K1957 specifically in HBV-positive HCC tissues. Alanyl-tRNA synthetase 1 (AARS1) mediates SPTAN1-kla formation, while histone deacetylase 1 (HDAC1) acts as a delactylase. HBV infection enhances lactate production by inducing the expression of HK2, promoting SPTAN1-kla formation, and disrupting the liquid-liquid phase separation (LLPS) of cytoplasmic SPTAN1, thereby facilitating its nuclear translocation. Within the nucleus, SPTAN1-kla interacts with core-binding factor β (CBFB) to activate NOTCH1/HES1 signaling, thereby promoting HCC cell proliferation. Furthermore, SPTAN1-kla activates the COX2/mPGES1 pathway through NOTCH1/HES1 signaling, thereby enhancing the biosynthesis of prostaglandin E2 (PGE2) and increasing the infiltration of exhausted CD8⁺ T cells. Therapeutic targeting of SPTAN1-kla using specific inhibitory peptides significantly attenuates HCC tumor growth in preclinical models. Our research identifies SPTAN1-kla as a novel oncogenic driver in HBV-related HCC, functioning via metabolic reprogramming and immune modulation. These findings position SPTAN1-kla as a promising therapeutic target for developing precision interventions against HBV-related HCC.