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.