Early-Life Hydrogen Sulfide Signaling as a Target for Cardiovascular-Kidney-Metabolic Syndrome Reprogramming.

Hydrogen sulfide (HS), once regarded solely as a toxic gas, is now recognized as a vital endogenous signaling molecule with important roles in both health and disease. Growing evidence supports the developmental origins of health and disease (DOHaD) framework, in which early-life disturbances in HS signaling may drive the later development of cardiovascular-kidney-metabolic (CKM) syndrome-a condition that encompasses chronic kidney disease, obesity, diabetes, and cardiovascular disease. This review highlights the emerging importance of HS in CKM programming and the potential of HS-based interventions during gestation and lactation to prevent long-term adverse health outcomes in offspring. Findings from animal studies suggest that maternal supplementation with sulfur-containing amino acids, -acetylcysteine, HS donors, and related sulfur-containing biomolecules can attenuate CKM-related risks in progeny. Despite these advances, several critical areas remain underexplored, including the role of gut microbiota-derived HS, the epigenetic mechanisms influenced by HS during development, and the clinical translation of preclinical findings. Targeting HS signaling offers a promising strategy for early-life prevention of CKM syndrome and may also hold broader potential for preventing other DOHaD-related chronic diseases.