Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. However, the molecular mechanisms underlying septic cardiomyopathy remain elusive. Irisin is a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) that protects the heart from ischemia/reperfusion injury through upregulation of mitochondrial ubiquitin ligase (MITOL). Gasdermin D (GSDMD)-dependent pyroptosis plays a pivotal role in septic cardiomyopathy by regulating mitochondrial homeostasis. However, whether irisin can regulate MITOL to inhibit GSDMD-dependent pyroptosis in septic cardiomyopathy is yet to be investigated. Thus, this study was designed to explore the role of irisin in septic cardiomyopathy and its underlying molecular mechanisms. Our results demonstrate that irisin improves cardiac function against sepsis-induced cardiac dysfunction by reducing cardiac inflammation and myocardial pyroptosis. Using MITOL siRNA in vitro, the results revealed that the protective role of irisin against lipopolysaccharide (LPS)-induced cell injury was mediated by MITOL activation and the resulting inhibition of GSDMD-dependent pyroptosis. Moreover, irisin alleviated LPS-induced H9c2 cell injury by suppressing IL-1β expression and reducing serum LDH and CK-MB concentrations in a MITOL/GSDMD-dependent manner. Collectively, our data suggest that irisin treatment ameliorates cardiac dysfunction in septic cardiomyopathy by activating MITOL and inhibiting GSDMD-dependent pyroptosis. These findings highlight the clinical relevance and therapeutic potential of irisin and MITOL for the management of sepsis-induced cardiac dysfunction.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.