Forsythoside A attenuates sepsis-induced cardiomyopathy by modulating macrophage polarization via Nrf2/NF-κB...

Sepsis-induced cardiomyopathy (SICM) is a major manifestation of sepsis-related multiple organ dysfunction, driven by uncontrolled inflammation, oxidative stress, and disrupted macrophage polarization. However, the mechanisms by which immune dysregulation contributes to myocardial injury remain incompletely understood. This study investigated whether Forsythoside A (FTA), a phenylethanoid glycoside from Forsythia suspensa, attenuates SICM by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated inhibition of nuclear factor-κB (NF-κB), thereby reprogramming macrophage M1/M2 polarization and secondarily reducing myocardial oxidative stress and apoptosis. An LPS-induced murine model of SICM and macrophage-cardiomyocyte coculture systems were established to evaluate the cardioprotective effects of FTA. FTA significantly improved cardiac function, reduced myocardial injury, and attenuated oxidative stress and cardiomyocyte apoptosis. Mechanistically, molecular docking and transcriptomic analyses suggested the potential involvement of Nrf2-related signaling in the effects of FTA. FTA activated the Nrf2/HO-1/NQO1 antioxidant pathway while suppressing NF-κB activation, thereby promoting a shift in macrophage polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. Pharmacological inhibition of Nrf2 using ML385 partially reversed these protective effects. Together, these findings demonstrate that FTA alleviates SICM by modulating macrophage polarization through an Nrf2-NF-κB signaling axis and may represent a promising natural cardioprotective candidate.