Frontiers in pharmacology · 2026
Tricholoma matsutake polypeptide modulates cardiac metabolism and restores autophagic flux to mitigate doxorubicin-induced senescence.
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Ye Ting, Wang Qiu-Shi, Ge Qian-Wen, Li Meng-Jiao, Yuan Yang, Sun Wen-She, Xing Dong-Ming
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: TMP functions as a metabolic modulator that protects against DIC by reprogramming energy metabolism and restoring mitochondrial quality control. These findings highlight TMP as a promising adjuvant for preserving cardiovascular health in cancer survivors.
METHODS: 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.
RESULTS: 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.
CONCLUSION: TMP functions as a metabolic modulator that protects against DIC by reprogramming energy metabolism and restoring mitochondrial quality control. These findings highlight TMP as a promising adjuvant for preserving cardiovascular health in cancer survivors.