Lactylated SPTAN1 Accelerates Hepatocellular Carcinoma Progression by Promoting NOTCH1/HES1 Activation and Immunosuppression

Abstract 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.