Interaction between post-tumor inflammation and vascular smooth muscle cell dysfunction in sepsis-induced cardiomyopathy.

BACKGROUND

Sepsis-induced cardiomyopathy (SIC) presents a critical complication in cancer patients, contributing notably to heart failure and elevated mortality rates. While its clinical relevance is well-documented, the intricate molecular mechanisms that link sepsis, tumor-driven inflammation, and cardiac dysfunction remain inadequately explored. This study aims to elucidate the interaction between post-tumor inflammation, intratumor heterogeneity, and the dysfunction of VSMC in SIC, as well as to evaluate the therapeutic potential of exercise training and specific pharmacological interventions.

METHODS

Transcriptomic data from NCBI and GEO databases were analyzed to identify differentially expressed genes (DEGs) associated with SIC. Weighted gene co-expression network analysis (WGCNA), gene ontology (GO), and KEGG pathway enrichment analyses were utilized to elucidate the biological significance of these genes. Molecular docking and dynamics simulations were used to investigate drug-target interactions, and immune infiltration and gene mutation analyses were carried out by means of platforms like TIMER 2.0 and DepMap to comprehend the influence of DVL1 on immune responsiveness.

RESULTS

Through the utilization of the datasets, we discovered the core gene DVL1 that exhibited remarkable up-regulated expression both in SIC and in diverse kinds of cancers, which were associated with poor prognosis and inflammatory responses. Molecular docking revealed that Digoxin could bind to DVL1 and reduce oxidative stress in SIC. The DVL1 gene module related to SIC was identified by means of WGCNA, and the immune infiltration analysis demonstrated the distinctive immune cell patterns associated with DVL1 expression and the impact of DVL1 on immunotherapeutic resistance.

CONCLUSIONS

DVL1 is a core regulator of SIC and other cancers and, therefore, can serve as a therapeutic target. The present study suggests that targeted pharmacological therapies to enhance response to exercise regimens may be a novel therapeutic tool to reduce the inflammatory response during sepsis, particularly in cancer patients. The identified drugs, Digoxin, require further in vivo and clinical studies to confirm their effects on SIC and their potential efforts to improve outcomes in immunotherapy-resistant cancer patients.