Neferine Mitigates Hyperthyroid-induced Cardiac Dysfunction via Modulation of STAT Signaling: An Experimental Animal Study

Background Prolonged elevation of thyroid hormone levels leads to cardiomyocyte hypertrophy, tissue fibrosis, and altered cardiac electrophysiology. Abnormal activation of the Signal Transducer and Activator of Transcription (STAT) signaling pathway plays a significant role in hyperthyroid heart disease. Purpose The aim of this study was to investigate whether neferine (Nef) administration is an effective intervention. Materials and Methods Sprague-Dawley rat models of myocardial injury were established via intraperitoneal injection of levothyroxine for 4 weeks. Body weight (BW) was recorded weekly. At the beginning of week 5, the electrocardiographic examination was performed after the animals in each group were anesthetized. Heart weight (HW) and HW Index (HW/BW) were calculated. Cardiac tissues underwent histopathological examination, Western Blot analysis of IL-6/gp130/STAT3, and enzyme-linked immunosorbent assay (ELISA) detection of IL-6Rα. Results Compared with control rats, hyperthyroid model rats exhibited significantly decreased BWs, increased HW indices, and abnormal electrocardiogram changes, whereas Nef treatment alleviated these abnormalities. Histopathology revealed increased cardiac fibrosis in hyperthyroid rats, and Nef significantly attenuated myocardial hypertrophy and fibrosis. The percentage of collagen fibers in the hyperthyroidism model group was 7.23% ± 1.75%, whereas it decreased to 3.96% ± 1.14% and 1.52% ± 0.64% in the groups treated with medium and high doses of Nef. The expression of IL-6/IL-6Rα/gp130/STAT3 was significantly upregulated in the hyperthyroid myocardium, and Nef also exerted antagonistic effects. Nef had no significant effect on normal rats. Conclusion Hyperthyroid cardiomyopathy increases myocardial IL-6/IL-6R (α&β)/STAT3 levels. Nef dose-dependently mitigates these abnormalities, with high-dose treatment restoring parameters to near-normal ranges. Nef also significantly mitigates myocardial fibrosis and cardiac electrophysiological dysfunction.