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Hua-Xi Zou,1,2,* Tie Hu,1,2,* Jia-Yi Zhao,2,3,* Bai-Quan Qiu,2,4 Chen-Chao Zou,2,4 Qi-Rong Xu,1 Ji-Chun Liu,1,2 Song-Qing Lai,1,2 Huang Huang1,2 1Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Medical Innovation Experimental Program, Huan Kui College, Nanchang University, Nanchang, People’s Republic of China; 4Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huang Huang; Song-Qing Lai, Email jack19871212@hotmail.com; ndyfy03743@ncu.edu.cnIntroduction: Sepsis is currently a common condition in emergency and intensive care units, and is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Cardiac dysfunction caused by septic myocardial injury (SMI) is associated with adverse prognosis and has significant economic and human costs. The pathophysiological mechanisms underlying SMI have long been a subject of interest. Recent studies have identified ferroptosis, a form of programmed cell death associated with iron accumulation and lipid peroxidation, as a pathological factor in the development of SMI. However, the current understanding of how ferroptosis functions and regulates in SMI remains limited, particularly in the absence of direct evidence from human heart.Methods: We performed a sequential comprehensive bioinformatics analysis of human sepsis cardiac transcriptome data obtained through the GEO database. The lipopolysaccharide-induced mouse SMI model was used to validate the ferroptosis features and transcriptional expression of key genes.Results: We identified widespread dysregulation of ferroptosis-related genes (FRGs) in SMI based on the human septic heart transcriptomes, deeply explored the underlying biological mechanisms and crosstalks, followed by the identification of key functional modules and hub genes through the construction of protein-protein interaction network. Eight key FRGs that regulate ferroptosis in SMI, including HIF1A, MAPK3, NOX4, PPARA, PTEN, RELA, STAT3 and TP53, were identified, as well as the ferroptosis features. All the key FRGs showed excellent diagnostic capability for SMI, part of them was associated with the prognosis of sepsis patients and the immune infiltration in the septic hearts, and potential ferroptosis-modulating drugs for SMI were predicted based on key FRGs.Conclusion: This study provides human septic heart transcriptome-based evidence and brings new insights into the role of ferroptosis in SMI, which is significant for expanding the understanding of the pathobiological mechanisms of SMI and exploring promising diagnostic and therapeutic targets for SMI.Keywords: septic myocardial injury, ferroptosis, heart transcriptome, key genes, database

Additional file 1. Additional figures and tables.