PCSK9 Exhibits Novel Nuclear Localization in LSEC and Its Targeting with Bioinspired Nanoparticles Reduces Colorectal Liver Metastasis
Background & AimsColorectal cancer liver metastasis is the leading cause of mortality in affected patients, with liver sinusoidal endothelial cells playing a pivotal role in metastatic niche formation. Proprotein convertase subtilisin/kexin type 9 has emerged as a regulator of tumor biology, but its function in the hepatic microenvironment remains poorly defined. This study aimed to characterize the role and subcellular localization of PCSK9 in liver sinusoidal endothelial cells and to evaluate the therapeutic potential of its endothelial-specific inhibition in colorectal liver metastasis. MethodsIn vitro studies were performed using human and murine liver sinusoidal endothelial cells stimulated with conditioned media from metastatic colorectal cancer cells and cancer stem cells. Subcellular localization was assessed by immunofluorescence, immunogold electron microscopy, and biochemical fractionation. Protein interactions were investigated using co-immunoprecipitation and proteomic analyses. For in vivo validation, a murine model of colorectal liver metastasis was generated by intrasplenic injection of tumor cells, followed by systemic administration of chondroitin sulfate-targeted nanoparticles delivering PCSK9 siRNA every 5 days for 18 days. ResultsPCSK9 was consistently expressed in liver sinusoidal endothelial cells and displayed a predominant nuclear localization, which increased upon tumor-induced activation. Proteomic integration identified multiple candidate interacting proteins involved in metabolic and tumor-related pathways. Targeted nanoparticle-mediated delivery achieved efficient PCSK9 silencing in vitro. In vivo, endothelial-specific PCSK9 inhibition significantly reduced liver metastatic tumor burden compared with control groups, whereas free siRNA showed no significant effect. ConclusionsPCSK9 exhibits a novel nuclear localization in liver sinusoidal endothelial cells and potentially interacts with proteins implicated in tumor mediated pathways. Selective inhibition of endothelial PCSK9 using targeted nanoparticles significantly reduces colorectal liver metastasis, highlighting a novel therapeutic strategy focused on the hepatic microenvironment. Impact and ImplicationsThis study provides mechanistic insight into how PCSK9 contributes to colorectal liver metastasis by identifying its novel nuclear localization and potential function in liver sinusoidal endothelial cells. These findings are important for researchers and clinicians seeking to understand microenvironment-driven metastasis and resistance to current therapies. The demonstration that endothelial-specific targeting of PCSK9 reduces metastatic burden suggests a new avenue for therapeutic development beyond systemic inhibition. Such strategies could be translated into precision nanomedicine approaches to improve outcomes in patients with metastatic colorectal cancer while minimizing off-target effects.