肝细胞癌（HCC）具有高患病率和恶劣预后的特点，是全球癌症相关死亡的主要原因。作为肝癌细胞的一个亚群，具有分化、肿瘤发生和自我更新能力的肝癌干细胞（LCSCs）是导致HCC进展和治疗抵抗的原因之一。因此，对与LCSCs相关的新型分子生物标志物的深入探索非常必要。在我们的研究中，我们发现人类AlkB同源物H5（ALKBH5）在LCSCs中富集表达，能够促进HCC细胞的增殖、侵袭和迁移。在机械上，ALKBH5通过去甲基化的方式正向调控SOX4的表达，而SOX4则通过转录水平上调SHH的表达来激活Sonic Hedgehog（SHH）信号通路。此外，从CD133+ HCC细胞衍生的外泌体可以将ALKBH5传递到THP-1细胞，这可能与巨噬细胞M2极化相关。总之，ALKBH5 / SOX4轴通过激活SHH信号通路在加重LCSC特性方面发挥了重要作用，并且ALKBH5可能是与巨噬细胞M2极化相关的关键效应物。这些发现可能为HCC的诊断和治疗提供了有前途的新生物标志物。© 2023年。作者（作者）在施普林格-费尔拉格GmbHH德国的独家许可下，属于施普林格自然出版集团的一部分。

Hepatocellular carcinoma (HCC), featured with high prevalence and poor prognosis, is the major cause of cancer-related deaths worldwide. As a subgroup of liver cancer cells capable of differentiation, tumorigenesis and self-renewal, liver cancer stem cells (LCSCs) serve as one of the reasons leading to HCC progression and therapeutic resistance. Therefore, in-depth exploration of novel molecular biomarkers related to LSCSs is of great necessity. In our study, we found that human AlkB homolog H5 (ALKBH5) expression was enriched in LCSCs, which could foster proliferation, invasion and migration of the HCC cells. Mechanically, ALKBH5 positively mediated the expression of SOX4 via demethylation, and SOX4 promoted SHH expression at the transcriptional level to activate sonic hedgehog (SHH) signaling pathway. Furthermore, exosomes derived from CD133+ HCC cells could transmit ALKBH5 into THP-1 cells, which might be associated with M2 polarization of macrophages. In summary, the ALKBH5/SOX4 axis plays a significant role in exacerbating LCSC properties via activating SHH signaling pathway, and ALKBH5 could be a critical effector related to macrophage M2 polarization. These findings might provide a promising new biomarker for HCC diagnosis and treatment.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.