Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition of telomerase activity, reduction in telomere lengths, enhanced senescence and suppressed tumor cell proliferation and growth in mice. Lipid nanoparticle-mediated delivery of FBP1 mRNA inhibits liver tumor growth. Additionally, FBP1 expression levels inversely correlate with TERT pSer227 levels in renal and hepatocellular carcinoma specimens and with poor prognosis of the patients. These findings demonstrate that FBP1 governs cell immortality through its protein phosphatase activity and uncover a unique telomerase regulation in tumor cells attributed to the downregulation or deficiency of FBP1 expression.

端粒功能障碍与衰老过程密切相关，并且是一个突出的癌症标志。在这里，我们证明端粒酶活性在癌症和正常细胞中受到差异性调节，具体取决于果糖-1,6-双磷酸酶 1 (FBP1) 的表达状态。在表达 FBP1 的细胞中，FBP1 直接与端粒酶逆转录酶 (TERT) Ser227 相互作用并使其去磷酸化。去磷酸化的 TERT 无法转位到细胞核中，导致小鼠端粒酶活性受到抑制、端粒长度缩短、衰老加速并抑制肿瘤细胞增殖和生长。脂质纳米颗粒介导的FBP1 mRNA 递送抑制肝肿瘤生长。此外，FBP1 表达水平与肾癌和肝细胞癌标本中的 TERT pSer227 水平呈负相关，且与患者的不良预后相关。这些发现表明，FBP1 通过其蛋白磷酸酶活性控制细胞永生，并揭示了肿瘤细胞中由于 FBP1 表达下调或缺陷而产生的独特端粒酶调节。