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Liver cancer is the fourth most common cause of cancer related deaths, ranking sixth in terms of incidence rate, and hepatocellular carcinoma (HCC) is the main type of liver cancer. Hepatitis B virus (HBV) infection is the main cause of HCC, and currently, HBV related HCC has become an important public health issue. COL15A1 encodes the alpha chain of collagen XV, a member of the FACIT collagen family, which has anti-angiogenic and anti-tumoral properties and play a vital role in tissue homeostasis in the liver, and its specific function in HBV-related HCC still needs further exploration. This study aimed to determine the regulatory role of COL15A1 in HBV-related HCC and explored the underlying mechanisms at the cellular level. Firstly, the biochip analysis results showed that the expression of COL15A1 was increased in human HBV-related HCC tissues. Furthermore, HBV induction also could significantly increase the expression of COL15A1 in hepatoma cell lines. Functionally, it found that COL15A1 silencing could significantly inhibit apoptosis and promote proliferation, migration, invasion and growth of HepG2.2.15. Mechanically, it found that COL15A1 could interact with P4HB，and its silencing could significantly increase the expression level of P4HB, thereby inhibiting the GRP76 expression and promoting growth and malignancy of HepG2.2.15 cells, revealing COL15A1 might play an anticancer role in HBV-related HCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yunhong Xia reports financial support was provided by The Natural Science Foundation of Anhui Province, China (Grant Numbers: 2108085MH289)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)