Fenofibrate ameliorates LPS-induced cardiac injury through alleviation of ferroptosis

Ferroptosis-associated insults play a critical role in the pathological development of septic cardiomyopathy. Fenofibrate (Feno) is a fibrate drug used to treat high triglycerides and high cholesterol, however its pharmacological function in septic cardiomyopathy is not well understood.

We allocated 36 male C57BL/6J mice into four groups (n = 9/group): Vehicle, Feno, LPS, and LPS+Feno. Techniques included hematoxylin-eosin (HE) staining, LDH assay, ELISA, echocardiography, measurement of MDA, GSH, Fe2⁺, real-time PCR, and western blot analysis.

Administration of Feno significantly mitigated myocardial injury by reducing serum CK-MB levels from 963.8 U/L to 512.5 U/L, cTnI from 0.65 g/L to 0.36 g/L, and LDH from 552.4 U/L to 372.1 U/L. Feno improved cardiac function by increasing ejection fraction from 65.5% to 78.5% and fractional shortening from 42.3% to 57.3%. Feno also inhibited inflammatory cytokines IL-6 and TNF-α, reduced MDA levels, increased GSH levels, and restored GPX4, FTH1, and SLC7A11 expression. The protective effects of Feno may be associated with the YAP1 signaling pathway.

Our findings suggest that Feno has the potential to protect against LPS-induced cardiac injury through the alleviation of ferroptosis, offering a promising therapeutic strategy for septic cardiomyopathy. However, the study is limited by the use of a single animal model and the lack of translational data in humans.