Editorial: Perspectives in molecular viral pathogenesis

The discipline of molecular viral pathogenesis stands at a transformative juncture in 2025. For much of the late 20th and early 21st centuries, the field was defined by a reductionist focus on the acute replication cycle (Enquist, 2009;Fang and Casadevall, 2011). Research prioritized the "how" of viral entry, the "mechanics" of genome replication, and the "kinetics" of lytic exit. While this approach yielded the antiviral pharmacopeia currently in use, it has increasingly proven insufficient to explain the complex, multi-systemic, and chronic sequelae that characterize modern viral threats.We are now compelled to reconceptualize the virus not merely as a transient intracellular pathogen, but as a persistent and sophisticated engineer of the host's neuro-immuno-endocrine landscape. This shift is driven by the realization that the clinical footprint of a virus often extends years or even decades beyond the clearance of acute viremia. This reality has been brought into sharp focus by the global burden of Long COVID and mounting evidence linking viral pathogens to neurodegenerative and metabolic diseases. The articles collected in the "Perspectives in Molecular Viral Pathogenesis: 2025" Research Topic integrate these concepts, offering a cohesive picture of the virus as a master regulator of host equilibrium.A dominant theme in virology is the persistence of physiological disruption long 34 the acute infectious agent is ostensibly cleared. This represents a "zero-sum game" for the host: the cholesterol that should be converted into 79 testosterone via the Steroidogenic Factor 1 (SF-1) pathway is instead "stolen" to build viral 80 components. This metabolic theft provides a precise molecular explanation for the low testosterone 81 and HDL levels observed in severe COVID-19 patients and highlights possible therapeutic targets to prevent these effects. 83The interaction a virus and its host is, at its core, a physical event. Two articles in this collection illuminate how the manipulation of cellular architecture drives pathology. As we move forward, the integration of these molecular insights with clinical observation will be 114 essential for developing therapies that transcend simple viral suppression. Virology must evolve 115 toward restorative medicine, seeking not only to clear pathogens but to actively recalibrate disrupted 116 neuro-endocrine axes, fortify the functional synaptic architecture, and reclaim the metabolic assets 117 commandeered during infection. By shifting from a purely lytic view of infection toward a systems-118 biology perspective, we can begin to address the whole-body equilibrium that viruses so effectively 119 destabilize. This paradigm shift promises a new era of precision medicine, where the clinical 120 objective is not merely to eliminate the invader, but to repair and restore the complex biological 121 architecture that remains its primary target. 122 123 124