Sonlicromanol Mitigates Sepsis-induced Heart Injury via Mitochondrial and Pyroptosis Modulation

Sepsis-induced myocardial dysfunction (SIMD) is a severe consequence of systemic infection, primarily driven by mitochondrial dysfunction, inflammation, and pyroptosis. Sonlicromanol, a mitochondrial redox-modulating therapeutic agent, has shown promise in preserving mitochondrial function, but its role in sepsis-induced cardiac injury remains unclear. This study evaluates the protective effects of sonlicromanol in a rat model of sepsis-induced cardiac dysfunction, with a focus on mitochondrial dynamics, mitophagy, and inflammasome-pyroptosis pathways. Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Sonlicromanol (50 mg/kg/day) was administered intraperitoneally for 2 weeks before CLP. Rats were divided into five groups: (1) Control, (2) CLP, (3) CLP + sonlicromanol, (4) CLP + Mdivi-1 (mitophagy inhibitor), and (5) CLP + sonlicromanol + Mdivi-1. Cardiac function was evaluated via catheter-based pressure analysis, including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and left ventricular developed pressure (LVDP). Myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, and mitochondrial dynamics were assessed via enzyme-linked immunosorbent assay, H and E staining, Western blot, and mitochondrial fluorometric assays. CLP-induced septic rats showed reduced LVSP and LVDP, along with elevated LVEDP, cardiotroponin, and B-type natriuretic peptide, and significant myocardial damage. Pyroptosis markers (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3, cleaved caspase-1, gasdermin-D, interleukin-1 β, and lactate-dehydrogenase) were elevated, while mitophagy markers (PTEN-induced kinase 1 and Parkin) and mitochondrial function (membrane potential and adenosine triphosphate levels) declined. Sonlicromanol significantly improved cardiac function and injury markers, suppressed pyroptosis, restored mitochondrial dynamics (increased mitofusin-2, modulated dynamin-related protein 1), enhanced mitophagy, and improved mitochondrial function. Mdivi-1 co-treatment attenuated these effects, indicating a role for mitochondrial dynamics and mitophagy in sonlicromanol's efficacy. Sonlicromanol ameliorates SIMD by modulating mitochondrial homeostasis and inhibiting pyroptosis. These findings support sonlicromanol as a potential therapy for sepsis-related cardiac injury.