Ganoderma atrum polysaccharide inhibits ROS/NLRP3/pyroptosis axis by fixing mitochondrial dynamics disorder in PD-1 inhibitors-induced carditis of Lewis lung carcinoma mice

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.