IntroductionDiabetic cardiomyopathy (DCM) is a complication of diabetes mellitus (DM) that can lead to heart failure and increase the risk of mortality. Pedunculoside (PE), a novel triterpenoid saponin, exhibits anti-inflammatory and anti-oxidative stress (OS) properties. However, its role in DCM remains unexplored.MethodsDCM models were established and treated with PE or the Nrf2 inhibitor (ML385). In vitro, cell function was evaluated using CCK-8, flow cytometry, qRT-PCR, and ELISA. In vivo, fasting blood glucose and insulin levels in rats were measured. The effects of PE on DCM were assessed using HE staining, TUNEL staining, and corresponding kits. Additionally, Nrf2/HO-1 pathway proteins were analyzed by western blot.ResultsLow doses of PE (2.5, 5, 10, and 20 μM) did not affect the viability of H9c2 cells. PE (10 and 20 μM) improved cell viability and prevented apoptosis, inflammation, and OS in high glucose (HG)-stimulated H9c2 cells. PE also upregulated Nrf2 in the nucleus and enhanced HO-1 and NQO1 expression in HG-treated H9c2 cells. Furthermore, the Nrf2 inhibitor (ML385) reversed PE's protective effects on HG-induced cell injury. In vivo, PE reduced blood glucose, increased insulin, alleviated myocardial injury, inhibited apoptosis, decreased levels of inflammatory factors and OS, and upregulated Nrf2, HO-1, and NQO1 in DCM model rats.DiscussionPE alleviates DCM injury by activating the Nrf2/HO-1 pathway. These findings support the potential therapeutic application of PE in DCM.