Background: Hepatocellular carcinoma (HCC) remains among the most lethal malignancies worldwide, and acquired resistance to targeted therapy limits durable clinical benefit. Apatinib, a selective vascular endothelial growth factor receptor-2 inhibitor, is used in advanced HCC, but the contribution of the gut microbiota to Apatinib resistance remains incompletely defined. This study aimed to determine whether gut microbiota dysbiosis, particularly loss of Methods: A Hepa1-6 syngeneic subcutaneous HCC model was established in C57BL/6 mice. The apatinib-resistant phenotype was operationally defined by continued tumor growth under apatinib pressure together with an Results: Apatinib-resistant mice showed gut dysbiosis characterized by reduced microbial diversity, distinct beta-diversity clustering, and marked depletion of Akk. Resistant tumors exhibited reduced M1-like and increased M2-like macrophage fractions, together with lower phosphorylation of p65 and IκBα in whole-tumor lysates. Oral live Akk administration restored intestinal Akk abundance, reduced tumor volume and weight, re-established M1-like macrophage polarization, and reactivated tumor-level NF-κB signaling. In BMDMs exposed to apatinib-resistant Hepa1-6-conditioned medium, Akk supernatant and pasteurized Akk partially restored NF-κB phosphorylation and attenuated M2-like transcriptional skewing. Conclusions: Akk depletion accompanies an apatinib-resistant HCC phenotype and Akk-centered microbial modulation may help counteract resistance by reshaping macrophage-associated antitumor immunity. These findings support further validation of Akk-derived signals in community-level microbiome models and clinically relevant HCC settings.