ABSTRACT Anti-Sjögren's syndrome antigen A (SSA) autoantibodies are primarily found in patients with Sjögren's syndrome and systemic lupus erythematosus (SLE), where they represent a useful diagnostic marker whose pathological significance remains to be clarified. Importantly, the presence of anti-SSA autoantibodies in pregnant mothers associates with a high risk to bear children that develop neonatal lupus with irreversible damage of the heart conduction system. The development of congenital heart block secondary to maternal seropositivity for anti-SSA autoantibodies associates with child mortality rate of up to 30% and the requirement of a pacemaker within the first year of life in about 64% of the cases. This elevated morbidity and dire prognosis have not changed in years mainly because of the difficulty to reduce the burden of maternal anti- SSA autoantibodies that cause the damage to the fetal heart. Here we propose to inhibit SSA autoantibody production in pregnant mothers for the prevention of heart tissue injury in their fetuses. Building on preliminary data that identified leptin as a promoter of the production of anti-SSA autoantibodies in mice and that showed the efficacy of leptin inhibition in reducing circulating anti-SSA autoantibodies, we aim to test whether leptin antagonism in anti-SSA-positive pregnant mice can reduce fetal heart tissue injury in neonatal lupus, and delineate the underlying mechanisms. Goal of these studies is to have a preclinical proof-of-concept of a new modality of intervention in neonatal lupus, to improve outcomes and to limit the highly disabling/fatal consequences of this condition.