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Anti-citrullinated protein antibodies (ACPAs) are autoantibodies commonly observed in patients with rheumatoid arthritis (RA). Currently, most of the mechanisms of ACPA formation and bone destruction are well-understood, however, some unknown mechanisms still exist. There have been many new advances in ACPA-related clinical applications and targeted therapies. However, the existence of different ACPA subtypes is a limitation of targeted therapy. Herein, we present an overview of the process of ACPA generation, the underlying pathogenesis, and relevant clinical application and prospects.