OSCAR functions as a collagen I receptor to suppress hippo signaling and reprogram lipid metabolism in clear-cell renal cell carcinoma

Abstract Extensive extracellular matrix (ECM) remodeling is a hallmark of clear-cell renal cell carcinoma (ccRCC), and collagen I has been widely implicated in ccRCC progression through multiple oncogenic pathways. However, the receptor-level mechanisms by which collagen I engages specific signaling and metabolic programs remain incompletely understood. Here, we demonstrate that collagen I is highly expressed in ccRCC and predicts poor prognosis. We further uncover OSCAR as its key functional receptor, mediating tumor progression and metabolic reprogramming through Hippo signaling modulation. Mechanistically, collagen I binding induces OSCAR internalization and its interaction with the Hippo regulator SAV1. This disrupts SAV1 membrane localization, allowing YAP to enter the nucleus and activate downstream genes, which enhances proliferation, metastasis, and de novo fatty acid synthesis. Furthermore, we designed a lipid nanoparticle (CCP-LNP) that blocks the collagen I–OSCAR interaction and effectively suppresses tumor progression in vitro and in vivo. These findings reveal a collagen I–OSCAR–Hippo axis that links ECM signaling to metabolic reprogramming and suggest a potential therapeutic strategy for ccRCC.