TP53 links mitochondria-endoplasmic reticulum crosstalk and ferroptosis in septic cardiomyopathy: Protective modulation by nicorandil

Background: Septic cardiomyopathy (SCM) is a major contributor to sepsis-related mortality, with limited targeted therapies. Ferroptosis and mitochondria-associated endoplasmic reticulum membranes (MAMs) have emerged as important regulators of cardiac injury. TP53 can influence Ferroptosis and MAM function, but its role in SCM remains unclear. This study investigated the involvement of TP53 in MAM-associated Ferroptosis and the potential protective effects of nicorandil (Nic).

Methods: Bioinformatics analyses were performed to identify key SCM-related genes. Functional validation was conducted in LPS-induced H9C2 cells and a rat SCM model using pharmacological and genetic interventions, including Nic, GSK2656157, TP53 overexpression, and TP53 knockdown. Mitochondrial function, oxidative stress, calcium homeostasis, Ferroptosis, and ER-mitochondria interactions were assessed.

Results: TP53 was identified as a hub gene associated with Ferroptosis and mitochondrial-related pathways. LPS stimulation increased TP53 expression and transcriptional activity, accompanied by enhanced ER-mitochondria proximity, calcium dysregulation, oxidative stress, and ferroptosis-related changes. Nic significantly attenuated myocardial injury, reduced lipid peroxidation and iron accumulation, and restored GPX4 and SLC7A11 expression (P < 0.01). TP53 overexpression weakened these protective effects, whereas TP53 knockdown alleviated LPS-induced injury and ferroptosis-related changes. In addition, the Ferroptosis inhibitor ferrostatin-1 partially recapitulated the protective effects of Nic. Combined treatment with GSK further improved ER stress-related alterations and calcium homeostasis.

Conclusion: These findings suggest that TP53 is functionally involved in SCM and is associated with MAM-related alterations, calcium dysregulation, and Ferroptosis. Nic confers cardioprotective effects in vitro and in vivo, at least in part through modulation of TP53-associated stress signaling and Ferroptosis. Targeting TP53-related subcellular stress pathways may represent a potential therapeutic strategy for septic cardiomyopathy.