Paternal preconceptional metformin exposure induces metabolic dysregulation in offspring

Metformin, the first-line therapy for type 2 diabetes 1 , 2 , is increasingly used not only in diabetic patients but also being actively explored for cardiovascular risk reduction, anti-neoplastic effects, with real-world adoptions in healthy individuals for metabolic risk management and healthy aging 3 , 4 , 5 . While the Paternal Origins of Health and Disease (POHaD) paradigm posits that preconceptional environmental exposures in fathers can reprogram offspring health through epigenetic modifications in sperm 6 , 7 , 8 , 9 , the intergenerational consequences of paternal metformin use remain elusive. Recent clinical debates have focused on whether paternal metformin exposure increases the risk of genital malformations in male offspring; however, findings remain conflicting, with a Danish registry study reporting a positive association 10 while larger multinational cohorts found no such link 11 . Crucially, against the backdrop of the POHaD paradigm, beyond the risk of congenital malformations, the intergenerational impact of paternal metformin use on offspring metabolism, particularly via epigenetic mechanisms, remains unknown.