RNA-binding proteins (RBPs) closely regulate the whole lifecycle of most RNA molecules, from the very early stage of transcription to RNA decay. Dysregulation of RBPs significantly affects the fate of cancer-related transcripts. Therefore, it is imperative to fully understand the complicated RBP-RNA regulatory networks in malignant diseases and to explore novel therapeutic targets. The RBP DAZAP1 (deleted in azoospermia-associated protein 1), originally identified as an important protein in spermatogenesis, had rarely been studied in the context of carcinogenesis. The role of DAZAP1 in hepatocellular carcinoma (HCC) was unveiled in this study. The relative expression of DAZAP1 was significantly upregulated in HCC and was positively associated with several key malignant characteristics and poor postoperative survival in patients. DAZAP1 knockdown by small interfering RNA markedly inhibited HCC cell proliferation, migration and invasion. Furthermore, DAZAP1 significantly reduced cellular sensitivity to sorafenib (SF), which had been proven to be an inducer of ferroptosis by targeting the system Xc⁻ (composed of a light chain, xCT/SLC7A11, and a heavy chain, 4F2 heavy chain). At the mechanistic level, DAZAP1 was identified as a potent inhibitor of ferroptosis and an efficient binding partner of SLC7A11 mRNA. Further study revealed that DAZAP1 interacted with the 3′UTR (untranslated region) of SLC7A11 mRNA and positively regulated its stability. In our work, we clarified novel functions of DAZAP1 and preliminarily revealed its underlying mechanism in ferroptosis, which may be conducive to the exploration of biomarkers and therapeutic targets in HCC patients.

RNA 结合蛋白 (RBP) 密切调节大多数 RNA 分子的整个生命周期，从转录的早期阶段到 RNA 衰变。RBP 的失调显着影响癌症相关转录物的命运。因此，充分了解恶性疾病中复杂的RBP-RNA调控网络并探索新的治疗靶点势在必行。RBP DAZAP1（在无精子症相关蛋白 1 中缺失），最初被确定为精子发生中的一种重要蛋白质，很少在致癌作用的背景下进行研究。本研究揭示了 DAZAP1 在肝细胞癌 (HCC) 中的作用。DAZAP1 的相对表达在 HCC 中显着上调，并且与患者的几个关键恶性特征和较差的术后生存率呈正相关。小干扰 RNA 敲低 DAZAP1 可显着抑制 HCC 细胞增殖、迁移和侵袭。此外，DAZAP1 显着降低了细胞对索拉非尼 (SF) 的敏感性，索拉非尼 (SF) 已通过靶向系统 Xc 被证明是铁死亡的诱导剂^-（由轻链 xCT/SLC7A11 和重链 4F2 重链组成）。在机制水平上，DAZAP1 被鉴定为铁死亡的有效抑制剂和SLC7A1 1 mRNA的有效结合伴侣。进一步的研究表明，DAZAP1 与SLC7A1 1 mRNA的 3'UTR（非翻译区）相互作用并正调节其稳定性。在我们的工作中，我们阐明了 DAZAP1 的新功能，并初步揭示了其在铁死亡中的潜在机制，这可能有助于探索 HCC 患者的生物标志物和治疗靶点。