Diabetic cardiomyopathy (DCM) is a severe myocardial complication of diabetes mellitus, currently lacking specific therapeutic strategies. Pinoresinol diglucoside (PDG), an active lignan derived from the traditional medicine Eucommia ulmoides, was investigated for its protective role against DCM. Initially, a combination of network pharmacology, bioinformatics, machine learning algorithms, and molecular docking was utilized to identify potential targets. This computational analysis revealed that STIM1, Orai1, and NFAT3 are key targets, with PDG showing a strong binding affinity to these proteins.

Subsequent in vivo experiments using leptin receptor-deficient db/db mice demonstrated that PDG administration significantly improved cardiac systolic and diastolic function. It effectively attenuated cardiac hypertrophy, reduced the heart weight to tibia length ratio, and suppressed the expression of hypertrophic markers (Anp, Bnp, β-Mhc). Additionally, PDG markedly reduced the inflammatory response by downregulating Il-6, Tnf-α, and Il-1β, and inhibited cardiomyocyte apoptosis by decreasing cleaved caspase-3 and caspase-8 levels. Consistently, in vitro experiments using high glucose-stimulated H9c2 cells confirmed that PDG suppressed hypertrophy, inflammation, and apoptosis.

Mechanistically, PDG significantly downregulated the protein expression of STIM1 and Orai1, which consequently inhibited store-operated calcium entry (SOCE) and reduced the activation of the downstream transcription factor NFAT3. Furthermore, siRNA-mediated silencing of STIM1 or Orai1 reversed high glucose-induced cellular injuries, and the addition of PDG did not produce additive effects, confirming that PDG exerts its cardioprotective action specifically through the STIM1/Orai1/NFAT3 pathway. By mitigating calcium dysregulation, PDG ultimately inhibits the progression of DCM, highlighting its potential as a promising therapeutic candidate.

The work entitled “Pinoresinol diglucoside from Eucommia ulmoides attenuates diabetic cardiomyopathy through suppressing the store-operated calcium entry and downregulating the STIM1/Orai1/NFAT3 signaling pathway” was published on Chinese Journal of Natural Medicines (published on July 20, 2026).
DOI: 10.1016/S1875-5364(26)61114-4