Targeting the 4-HNE-H₂S pathway as a therapeutic strategy for placental injury in pregnancy with MAFLD.

This study aims to investigate the molecular mechanisms by which 4-hydroxynonenal (4-HNE) regulates hydrogen sulfide (H₂S)-producing enzymes, mediating the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) during pregnancy, thereby offering novel molecular targets for early diagnosis and intervention of related disorders. By establishing a MAFLD pregnant mouse model, we comprehensively examined the regulatory effects of 4-HNE on placental function and its interaction with the H₂S system. We found that MAFLD pregnant mice exhibited significant glucose metabolic disorders, hepatic steatosis, and placental damage. Mechanistically, 4-HNE disrupts H₂S biosynthesis, thereby impairing its inhibitory effect on the inflammasome pathway while simultaneously activating inflammatory cascades. This synergistic action exacerbates placental pathological damage, manifesting as abnormal vascular function and impaired materno-fetal exchange. Notably, exogenous H₂S intervention partially reversed 4-HNE-induced toxicity, suggesting the therapeutic potential of targeting this pathway. These findings demonstrate the pivotal role of the "4-HNE-H₂S-NLRP3" regulatory axis in MAFLD-associated placental injury, providing novel mechanistic insights and potential therapeutic targets for pregnancy complications.