Serum lipidome remodeling in viral pneumonia: from pathophysiology to therapeutics

Viral pneumonia remains a preeminent global health threat, frequently culminating in acute respiratory distress syndrome (ARDS) and systemic organ failure. While traditional paradigms have centered on protein-based inflammatory cascades, this review synthesizes a vast body of emerging evidence to redefine viral pneumonia as a profound systemic metabolic crisis, specifically characterized by the radical remodeling of the host lipidome. Based on a meta-synthesis of clinical and mechanistic data, we delineate a consistent "metabolic crash" during severe infection, where a precipitous decline in serum low-density lipoprotein (LDL)-cholesterol and the functional conversion of high-density lipoprotein (HDL) from a protective "immunometabolic shield" into a pro-inflammatory vehicle serve as decisive prognostic indicators. We further dissect the molecular mechanisms of this reprogramming, detailing how respiratory viruses hijack the host SREBP-SCAP axis to repurpose lipid droplets for viral assembly, while simultaneously triggering ferroptotic cell death through the exhaustion of the GPX4-lipid-peroxidase defense system. By integrating the "gut-lipid-lung axis" and the role of systemic metainflammation, we illustrate how the host's baseline metabolic architecture dictates the threshold for lethal alveolar-capillary barrier failure. Finally, we evaluate the therapeutic potential of restoring lipid homeostasis through specialized pro-resolving mediators (SPMs) and metabolic stabilizers. We conclude that transitioning toward a lipid-centric precision medicine model, supported by AI-driven metabolic endotyping, is essential for advancing host-directed therapies in the management of severe respiratory viral infections.