Background <p>The Homeobox (HOX) gene family is capable of binding to specific deoxyribonucleic acid (DNA) sequences, thereby modulating gene expression through activation or repression, which subsequently influences cellular behaviors including proliferation, adhesion, differentiation, and metastasis. Nevertheless, the role of Homeobox D10 (HOXD10) in the prognosis and progression of hepatocellular carcinoma (HCC) remains to be elucidated.</p> Methods <p>The expression of HOXD10 in HCC was subsequently validated through Western blot and immunohistochemistry analysis. The functional role of HOXD10 in HCC was evaluated using a combination of high- and low-expression experiments, incorporating both in vitro and in vivo methodologies. Furthermore, The Cancer Genome Atlas (TCGA) database was employed to investigate the functional networks related to HOXD10. The research specifically investigated the relationship between HOXD10 expression and cancer stem cells (CSCs), emphasizing the role of N6-methyladenosine (m6A) methylation and the PI3K/AKT/mTOR signaling pathway in hepatocellular carcinoma (HCC).</p> Results <p>The marked upregulation of HOXD10 expression in HCC suggests its potential impact on adverse prognostic outcomes. Furthermore, HOXD10 expression exhibited a significant association with the T stage, vascular invasion, and histological grade of HCC. Elevated HOXD10 expression was found to significantly enhance HCC cell proliferation, invasion, and migration. Notably, there was a significant correlation between HOXD10 expression and the activation of m6A methylation, as well as the PI3K/AKT/mTOR signaling pathway.</p> Conclusion <p>The results of this study corroborate the hypothesis that HOXD10 serves as a novel biomarker for tumor progression in HCC. Furthermore, HOXD10 has the capacity to activate the PI3K/AKT/mTOR signaling pathway through the regulation of m6A RNA methylation levels, thereby facilitating the self-renewal of hepatic cancer stem cells (HCSCs).</p>