Abstract
Sugen kinase 495 (Sgk495), also known as Serine/Threonine Kinase 40 (STK40), is a pseudokinase previously implicated in T cell differentiation via regulation of Foxo transcription factors. However, its function and mechanism in lung squamous cell carcinoma (LUSC) remain unclear. Here, we report that Sgk495 is highly expressed in LUSC tissues and correlates with shorter disease-free survival in patients. Knockdown of Sgk495 significantly inhibited the proliferation, migration, and invasion of LUSC cells. Mechanistically, Sgk495 facilitates the binding of the E3 ubiquitin ligase COP1 to Foxo1, enhancing K48-linked polyubiquitination and subsequent proteasomal degradation of Foxo1. This process alleviates the tumor-suppressive effects of Foxo1, thereby promoting the oncogenic capabilities of LUSC cells in vivo. Our findings identify Sgk495 as an oncogene in LUSC acting through the COP1/Foxo1 axis, revealing a potential therapeutic target for this malignancy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-026-04267-6.