This finding provides specific molecular explanation for CREB3’s “dual functionality” in TACE resistance contexts: previous research demonstrated CREB3 can not only suppress AKT signaling through competitive insulin receptor binding, exerting tumor-suppressive effects (He et al., 2024), but also mediate donafenib resistance by transcriptionally activating ZFAS1 (Hou et al., 2024). Here, AKT1 is linked to neoplasm.