骨骼是肝细胞癌（HCC）中仅次于其他肝外转移部位的第二常见位置，由于治疗选择有限，与极为不良的预后有关。N6-甲基腺嘌呤（m6A）是涉及HCC的重要修饰，但是m6A修饰如何诱导HCC骨转移（BM）的确切机制仍不清楚。关于丰富的m6A RNA修饰引起HCC BM的关键调节因子是METTL3和YTHDF1。Anillin肌动蛋白结合蛋白（ANLN）在带有BM组织的HCC中的表达显著增高，其信使RNA（mRNA）稳定性通过METTL3和YTHDF1的m6A表观转录组调节得到增强。高表达METTL3和YTHDF1的核ANLN蛋白临床上与HCC患者的BM相关。此外，HCC BM可归因于核ANLN的过度表达，形成与SP1的转录复合体，增强KIF2C转录活性，以激活mTORC1通路，从而增加RANKL的表达，并使RANKL-OPG在骨微环境中的表达失衡，导致恶性肿瘤侵入骨组织。此外，通过DZNeP抑制ANLN m6A修饰可减弱HCC BM。这些数据为HCC中m6A表观转录组调节的BM的调节和联系提供有意义的理解，并定义了潜在有价值的治疗靶点。©作者。

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N6-methyladenosine (m6A) is a prominent modification involved in HCC, but the exact mechanisms on how m6A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m6A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1. The expression of Anillin actin-binding protein (ANLN) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m6A epitranscriptomic regulation by METTL3 and YTHDF1. High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m6A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m6A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.© The author(s).