头颈部鳞状细胞癌（HNSCC）一直是一种恶性肿瘤，临床疗效不佳，新出现的证据表明RNA结合蛋白（RBPs）与该疾病的演变有关。被归类为RBPs的K-同源结构域1（KHDC1）家族被证明与细胞生存和死亡密切相关。作为一个新的KHDC1成员，目前仅有一项研究在骨关节炎滑膜细胞中揭示了KHDC1L促进增殖的功能。然而，据我们所知，KHDC1L在人类肿瘤中的作用尚未完全探索。基于The Cancer Genome Atlas（TCGA）数据库和细胞系与该研究中正常对照组的比较，我们首次发现KHDC1L在HNSCC中过度表达。根据生物信息学分析，凋亡和P53途径在TCGA数据库的KHDC1L低表达组中显著富集。此外，通过体外实验验证，我们发现KHDC1L的上调可以促进HNSCC CAL27细胞的增殖，并抑制细胞凋亡。转录组测序确定下游差异表达基因在PI3K-AKT途径中显著富集。此外，我们通过Western blot验证，在KHDC1L上调组中，pAKT / AKT和Bcl-2表达水平增高，BAX的表达保持不变，Cas pase-3和PARP-1的活性降低。总之，我们的研究首创地阐明了KHDC1L通过AKT和Bcl-2途径促进HNSCC CAL27细胞的增殖并抑制细胞凋亡，为寻找HNSCC新的诊断和治疗靶点迈出了重要的一步。

Head and neck squamous cell carcinoma (HNSCC) remains a dreadful malignancy bearing poor clinical efficacy, with emerging evidences indicating RNA-binding proteins' (RBPs') relevance to the evolution of the disease. Categorized as RBPs, the K-homology domain-containing 1 (KHDC1) family is proved to be closely related to cell survival and death. As a novel KHDC1 member, only one study is currently available in osteoarthritis synovial cells to unveil KHDC1L's function of promoting proliferation. Nevertheless, to the best of our knowledge, the role of KHDC1L in human tumour is yet to be fully explored. On the basis of The Cancer Genome Atlas (TCGA) database and cell lines comparison with normal counterparts in this study, we first discovered KHDC1L to be overexpressed in HNSCC. According to bioinformatics analysis, apoptosis and P53 pathways were remarkably enriched in the KHDC1L low-expression group in TCGA database. Moreover, in vitro experiments were applied to verify that upregulation of KHDC1L could promote the proliferation and inhibit apoptosis in HNSCC cells CAL27. Transcriptome sequencing ascertained downstream differentially expressed genes to be significantly enriched in PI3K-AKT pathways. Furthermore, as validated by western blot, we found an elevated expression level of pAKT/AKT and Bcl-2, constant expression level of BAX, together with decreased activity of Caspase-3 and PARP-1 in the KHDC1L-upregulated group. In conclusion, our study pioneeringly elaborated that KHDC1L could promote proliferation and inhibit apoptosis in HNSCC cell CAL27 via AKT and Bcl-2 pathways, representing a crucial step for seeking a new diagnostic and therapeutic target in HNSCC.