Protective effects of polysaccharides derived from Panax ginseng and Codonopsis pilosula against doxorubicin-induced myocardial senescence

The roots of Panax ginseng and Codonopsis pilosula are utilized in traditional medicine as a water decoction to treat heart failure. This study evaluated the protective effects of water-soluble polysaccharides derived from the roots of these plants against doxorubicin (DOX)-induced cardiotoxicity and myocardial senescence. Water-soluble polysaccharides were extracted, purified, and structurally characterized. Their cardioprotective efficacy and underlying mechanisms were investigated using DOX-treated H9c2 cardiomyocytes and a murine model. Additionally, SAPS2 and PPP6C knockdown cell models were used to validate the associated molecular targets. Among the fractions (GPF 1-4 and CPF 1-3) purified from the aqueous extracts of P. ginseng and C. pilosula, GPF-2 and CPF-2 exhibited significant cardioprotective effects, effectively attenuating DOX-induced oxidative stress, apoptosis, and cardiac dysfunction, with GPF-2 showing relatively greater efficacy. GPF-2 and CPF-2 were found to inhibit membrane Toll-like receptors, thereby contributing to the restoration of the intracellular SAPS2/PPP6C phosphatase complex. This complex may dephosphorylate NF-κB and suppress senescence-associated inflammation. Silencing SAPS2 or PPP6C attenuated these protective effects. In vivo experiments further indicated that GPF-2 significantly ameliorated cardiac function and reduced myocardial structural damage. Structural analysis revealed that GPF-2 is a relatively low-molecular-weight, compact polysaccharide with a dominant fraction of approximately 24 kDa, whereas CPF-2 is a high-molecular-weight, heterogeneous polysaccharide with a broader distribution, including fractions exceeding 100 kDa. The relatively low molecular weight and structural features of GPF-2 may contribute to its enhanced protective effects against DOX-induced cardiac aging at lower doses, potentially through modulation of the TLRs/SAPS2/PPP6C/NF-κB signaling pathway. These findings provide pharmacological evidence that GPF-2 is more effective than CPF-2 in delaying DOX-induced myocardial senescence under the tested conditions.