Imidazopyridine Derivatives Modulate Lipid Droplet-Driven Immunometabolic Reprogramming in SARS-CoV-2-Induced Macrophage Inflammation

Immunometabolic reprogramming has emerged as a critical determinant of inflammation during SARS-CoV-2 infection, with lipid droplets (LDs) acting as dynamic hubs connecting lipid metabolism, oxidative stress, and inflammatory signaling. Here, we investigated the immunometabolic effects of two imidazopyridine derivatives (IDs), 4B and 4J, on macrophage activation induced by inactivated SARS-CoV-2 in vitro. At 10 μM, both IDs significantly reduced LD accumulation, PPARγ expression, prostaglandin E₂ (PGE₂) production, and H₂O₂ generation, accompanied by reduced secretion of TNF-α, IL-6, IL-12, IFN-γ, and IL-10, without affecting macrophage viability after 24 h. Notably, combined treatment with 4B and 4J at 2.5 μM each retained substantial biological activity, supporting a dose-sparing strategy. The coordinated reduction of PPARγ expression, LD accumulation, and PGE₂ production supports modulation of a PPARγ–LD–PGE₂ immunometabolic axis. Collectively, our findings identify imidazopyridine derivatives as promising immunometabolic modulators. Targeting lipid droplet-driven inflammation may therefore represent a potential strategy for further investigation in SARS-CoV-2-associated inflammation and other infectious diseases characterized by lipid metabolic dysregulation.