Tricholoma matsutake polypeptide modulates cardiac metabolism and restores autophagic flux to mitigate doxorubicin-induced senescence

Doxorubicin (Dox)-induced cardiotoxicity (DIC) is initiated by acute stress that triggers early senescence-like phenotypes and severe metabolic maladaptation, yet effective therapeutic interventions remain elusive. Tricholoma matsutake polypeptide (TMP), a bioactive component from a medicinal fungus, exhibits antioxidant properties, but its potential to modulate cardiac energy metabolism remains unexplored.

In vivo, Sprague-Dawley rats were administered Dox (20 mg/kg, i.p.) with or without TMP (200/400 mg/kg/day) for 7 days. Cardiac function was assessed via high-resolution echocardiography, and metabolic signatures were decoded using LC-MS/MS-based untargeted metabolomics. In vitro, H9c2 cardiomyocytes were co-treated with Dox (5 μM) and TMP (30 μg/mL). Senescence phenotypes (SA-β-gal), mitochondrial dynamics (JC-1/Fura-2AM), and energy metabolites (ATP/NAD+) were quantified. Mechanistic axes were interrogated via Western blotting.

TMP significantly attenuated Dox-induced cardiac dysfunction, interstitial fibrosis, and inflammation. Metabolomics revealed that TMP mitigated the glycolysis-dominant metabolic reprogramming, restored phospholipid homeostasis, and preserved the nucleotide pool. In cardiomyocytes, TMP antagonized premature senescence and suppressed ROS generation without compromising Dox's antitumor efficacy in MCF-7 cells.

Mechanistically, TMP alleviated the Dox-induced blockade of autophagic flux (restoring Beclin1/p-Parkin) and reactivated the AMPK/Sirt1/PGC-1α energy-sensing pathway, thereby preserving the ATP/NAD+ reserve. These findings highlight TMP as a promising adjuvant for preserving cardiovascular health in cancer survivors.

This study provides evidence that TMP functions as a metabolic modulator that protects against DIC by reprogramming energy metabolism and restoring mitochondrial quality control. While these results are promising, further research is needed to confirm efficacy in clinical settings. This work is intended for laboratory research purposes only and should not be used for medical advice or therapeutic recommendations.