SERPING1 encodes C1 esterase inhibitor (C1-INH), a key regulatory protein of the complement system, contact activation pathway, and fibrinolysis. It primarily inhibits proteases like C1r/C1s, MASP-1/MASP-2. and kallikrein, modulating inflammatory and coagulation cascades. Deficiencies or dysfunction of C1-INH due to SERPING1 mutations cause hereditary angioedema (HAE), characterized by episodic swelling in subcutaneous or submucosal tissues. Autoantibodies targeting SERPING1/C1-INH are rare but implicated in acquired angioedema (AAE), often associated with lymphoproliferative disorders or autoimmune conditions. These antibodies either neutralize C1-INH activity or accelerate its degradation, leading to unregulated bradykinin production and vascular leakage. Clinically, anti-SERPING1 antibodies are detected via ELISA or functional assays to differentiate AAE from HAE. Research also explores their role in autoimmune diseases like systemic lupus erythematosus, where complement dysregulation occurs. Therapeutic strategies include C1-INH replacement, kallikrein inhibitors, or immunosuppressants. Recent advances focus on monoclonal antibodies targeting pathway components (e.g., lanadelumab) and gene therapy to restore SERPING1 function. Understanding SERPING1 antibodies aids in diagnosing rare angioedema subtypes and developing targeted therapies.