Loss of LRP1 Promotes Hepatocellular Carcinoma Progression via UFL1‐Mediated Activation of NF‐κB Signaling

Abstract Low‐density lipoprotein receptor‐related protein‐1 (LRP1) is thought to be correlated with hepatocellular carcinoma (HCC) invasion and metastasis. However, the precise mechanism through which LRP1 contributes to HCC progression remains unclear. Here, lower LRP1 levels are associated with malignant progression, and poor prognosis in patients with HCC is shown. LRP1 knockdown enhances the tumorigenicity of HCC cells in vitro and in vivo, whereas overexpression of either LRP1 or its β‐chain has the opposite effect. Mechanistically, LRP1 knockdown promotes the binding of ubiquitin‐like modifier 1 ligating enzyme 1 (UFL1) to OGA and accelerates ubiquitin‐mediated OGA degradation, leading to increased O‐GlcNAcylation of nuclear factor‐kappa B (NF‐κB) and subsequent inhibition of pro‐apoptotic gene expression. Conversely, exogenously expressed truncated β‐chain (β∆) stabilizes OGA by disrupting the association between UFL1 and OGA, consequently abolishing the anti‐apoptotic effects of O‐GlcNAcylated NF‐κB. The findings identify LRP1, particularly its β‐chain, as a novel upstream control factor that facilitates the stabilization of the OGA protein, thereby suppressing NF‐κB signaling and attenuating HCC progression, thus suggesting a novel therapeutic strategy for HCC.