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Ganoderma atrum polysaccharide inhibits ROS/NLRP3/pyroptosis axis by fixing mitochondrial dynamics disorder in PD-1
Xiao-Yu Mu1, Sheng-Bin Chen2, Song-Yu Yang2
1State Key Laboratory of Food Science and Resources, Nanchang University, 235 Nanjing East Road, Nanchang 330047, China.
Abstract:
Mitochondria were critical for pathogenesis of PD-1 inhibitors-induced carditis, which was demonstrated to be the mechanism for Ganoderma atrum polysaccharide (PSG) against cardiomyopathy. Hence, the present study aimed to determine the role of PSG in controlling mitochondrial homeostasis in PD-1 inhibitors-induced carditis of Lewis lung carcinoma mice. Results showed that PSG significantly alleviated PD-1 inhibitors-induced cardiotoxicity without compromising their anti-tumor effects, as evidenced by inhibiting cardiac histopathological disorders, creatine kinase (CK) release, and tumor growth. PSG administration significantly ameliorated inflammation by reducing pro-inflammatory cytokine IL-1β release and NLRP3 expression. Meanwhile, the reduction of pyroptosis was demonstrated to be implicated in PSG-inhibited carditis evidenced by the decrease in Caspase-1, gasdermin D (GSDMD). Mechanistically, mitochondria were sites of ROS generation and NLRP3 inflammasome activation. Our results showed that PSG suppressed NLRP3-induced pyroptosis, which was associated with inhibition of ROS attack and mitochondrial protection by maintaining mitochondrial membrane potential, reversing a deficiency in mitochondrial fission, suppressing mitochondrial hyper-fusion, suggesting that ROS/NLRP3/pyroptosis axis was a vital process in avoiding mitochondrial dysfunction during PSG-mediated cardioprotection. Additionally, the modification of the redox system was also shown in the context of cardioprotection of PSG, by elevating antioxidant enzyme activities and suppressing lipid oxidation.
Insights
Ganoderma atrum polysaccharide (PSG) protects against PD-1 inhibitor cardiotoxicity by preserving mitochondrial function and reducing inflammation. This cardioprotection occurs without hindering anti-tumor efficacy, offering a promising therapeutic strategy.
Area of Science:
- Cardiovascular Research
- Immunology
- Mitochondrial Biology
Background:
- PD-1 inhibitors can cause cardiotoxicity, impacting cardiac function.
- Mitochondrial dysfunction is a key factor in PD-1 inhibitor-induced carditis.
- Ganoderma atrum polysaccharide (PSG) has shown potential in treating cardiomyopathy.
Purpose of the Study:
- To investigate the role of PSG in maintaining mitochondrial homeostasis during PD-1 inhibitor-induced carditis.
- To determine if PSG can alleviate cardiotoxicity without affecting anti-tumor activity.
- To elucidate the mechanisms underlying PSG's cardioprotective effects.
Main Methods:
- Lewis lung carcinoma mice treated with PD-1 inhibitors were administered PSG.
- Cardiac histopathology, creatine kinase (CK) levels, and tumor growth were assessed.
- Inflammatory markers (IL-1β, NLRP3, Caspase-1, GSDMD) and mitochondrial parameters (ROS, membrane potential, fission/fusion) were analyzed.
Main Results:
- PSG significantly reduced cardiotoxicity, cardiac damage, and CK release.
- PSG administration inhibited tumor growth, indicating preserved anti-tumor effects.
- PSG ameliorated inflammation by decreasing IL-1β and NLRP3, and reduced pyroptosis by lowering Caspase-1 and GSDMD.
- PSG protected mitochondria by inhibiting ROS, maintaining membrane potential, and regulating mitochondrial dynamics.
Conclusions:
- PSG effectively alleviates PD-1 inhibitor-induced cardiotoxicity through mitochondrial protection and suppression of the ROS/NLRP3/pyroptosis axis.
- PSG offers cardioprotection without compromising the anti-tumor efficacy of PD-1 inhibitors.
- PSG represents a potential therapeutic agent for managing cardiotoxicity associated with immunotherapy.
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