Future efforts should focus on: (1) developing antagonists that selectively block OPN binding to pro-fibrotic receptors (e.g. αvβ3); (2) employing nanocarriers to deliver OPN-silencing agents specifically to stellate cells or tumour-associated macrophages; and (3) leveraging OPN’s value as a biomarker—its elevated expression in HBV-related hepatocellular carcinoma correlates with metastasis and response to immunotherapy, supporting its use in patient stratification, treatment monitoring, and early diagnosis. Here, SPP1 is linked to hepatocellular carcinoma.