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

Hydrogen sulfide (H₂S), 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 H₂S 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 H₂S in CKM programming and the potential of H₂S-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, N-acetylcysteine, H₂S 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 H₂S, the epigenetic mechanisms influenced by H₂S during development, and the clinical translation of preclinical findings. Targeting H₂S 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.