Mechanistically, we find for the first time that puerarin inhibits overactivated Na+/H+ exchange isoform 1 (NHE1) in HF, which may improve HF by decreasing Na+ and Ca2+ ion concentrations and attenuating mitochondrial damage caused by calcium overload; on the other hand, puerarin inhibits the activation of the p38 pathway in HF, reduces the expressions of TGF-β and proinflammatory cytokines, and suppresses myocardial fibrosis. Here, SLC9A1 is linked to hydrops fetalis.