下咽鳞癌（HPSCC）是最具侵袭性的癌症之一，以其极差的预后而臭名昭著。然而，目前只有很少的分子生物学研究进行了。作为一种新型的表观遗传基因调控方法，N6-甲基腺苷（m6A）RNA修饰在HPSCC中发生。m6A脱甲基酶AlkB同源物5（ALKBH5）的表达在人体HPSCC中常常被下调。此外，我们发现ALKBH5通过m6A调控方式在HPSCC细胞中调控人类Toll样受体2（TLR2），从而抑制了细胞增殖。ALKBH5降低了TLR2的m6A修饰，这可以被m6A读头IGF2BP2和YTHDF1所识别。IGF2BP2促进TLR2 mRNA稳定性，而YTHDF1促进TLR2 mRNA翻译。本研究揭示了ALKBH5在TLR2调控中的重要作用，并为HPSCC中m6A去甲基化的mRNA提供了一个新的角色。在HPSCC中抑制ALKBH5的m6A修饰值得进一步进行临床研究。© 2023. 细胞死亡与分化协会（ADMC）。

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m6A) RNA modification occurs in HPSCC. The expression of the m6A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an m6A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m6A modification, which could be recognized by the m6A readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for m6A demethylation of mRNA in HPSCC. The inhibition of m6A modification of ALKBH5 in HPSCC deserves further clinical investigation.© 2023. Cell Death Differentiation Association (ADMC).