Paternal Obesity‐Induced H3K27me3 Elevation Leads to MANF‐Mediated Transgenerational Metabolic Dysfunction in Female Offspring

Abstract Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8‐cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78‐PERK‐EIF2α‐ATF4‐CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3‐deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high‐fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD‐F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3‐dependent epigenetic regulation. The present study also identifies the H3K27me3‐MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.