配对免疫球蛋白样2型受体β（PILRB）主要在调节先天免疫中发挥至关重要的作用，但PILRB是否与癌症有关尚不清楚。在这里，我们报告 PILRB 通过结合和稳定 IRS4 来增强 PI3K/AKT 通路，从而驱动胃肿瘤发生，IRS4 可以过度激活 PI3K/AKT 通路。首先，PILRB 水平在人胃癌（GC）标本中上调，并且与 GC 患者的不良预后相关。此外，我们的数据表明，PILRB 在体外和体内促进 GC 细胞的细胞增殖、集落形成、细胞迁移和侵袭。从机制上讲，PILRB 将去泛素化酶 OTUB1 募集至 IRS4，并缓解 IRS4 的 K48 连接泛素化，保护 IRS4 蛋白免受蛋白酶体介导的降解和随后 PI3K/AKT 通路的激活。重要的是，GC 标本中 PILRB 的水平与 IRS4 呈正相关。同时，我们还发现PILRB通过改变ABCA1和SCARB1的表达水平来重新编程胆固醇代谢，并且PILRB的表达赋予GC细胞对他汀类药物治疗的抵抗力。总而言之，我们的研究结果说明了 PILRB 在胃肿瘤发生中的致癌作用，为 GC 中 PI3K/AKT 信号传导的调节提供了新的见解，并将 PILRB 作为 GC 中辛伐他汀治疗耐药的生物标志物。© 2024。 。

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.© 2024. The Author(s).