泛素特异性肽酶 44 (USP44) 属于泛素特异性蛋白酶家族，在各种人类癌症的发生和进展中至关重要。然而，其生物学功能和甲状腺癌的潜在机制仍知之甚少。在这项研究中，我们观察到 USP44 在甲状腺癌中经常受到启动子高甲基化的下调，并发现其表达下降与患者生存率低密切相关。随后的体外和体内功能研究表明，USP44 通过阻碍细胞周期的 G1/S 转变，显着抑制甲状腺癌细胞的增殖。从机制上讲，USP44直接与p21相互作用并消除其K-48连接的多聚泛素化链，从而以不依赖于细胞周期的方式稳定p21蛋白。此外，p21 的拯救部分缓解了 USP44 耗竭引起的细胞周期提前和细胞增殖。综上所述，我们的研究结果表明，由于启动子高甲基化，USP44 在甲状腺癌中经常受到抑制，并且通过去泛素化稳定 p21，从而发挥肿瘤抑制因子的作用。© 作者。

Ubiquitin-specific peptidase 44 (USP44) belongs to the ubiquitin-specific protease family and is pivotal in the development and progression of tumors across various human cancers. However, its biological function and the underlying mechanisms in thyroid cancer remain poorly understood. In this study, we observed that USP44 was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent in vitro and in vivo functional studies revealed that USP44 substantially suppressed the proliferation of thyroid cancer cells by impeding the G1/S transition in cell cycle. Mechanistically, USP44 directly interacted with p21 and eliminated its K-48-linked polyubiquitination chain, thereby stabilizing p21 proteins in a cell cycle-independent manner. In addition, the rescue of p21 partially alleviated cell cycle advancement and cell proliferation induced by the depletion of USP44. Our findings, taken together, indicate that USP44 is frequently repressed in thyroid cancer due to promoter hypermethylation and functions as a tumor suppressor by stabilizing p21 via deubiquitination.© The author(s).