Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi‐Organ Dysfunction

ABSTRACT Long Covid is a post‐viral syndrome characterized by persistent symptoms targeting multiple organ systems after initial SARS‐CoV‐2 infection. Current literature suggests that the mechanisms causing Long Covid involve viral persistence, immune dysregulation, systemic inflammation, endothelial dysfunction, and metabolic disturbances. By forming reservoirs in the tissues of various organs, SARS‐CoV‐2 may evade immunological clearances while triggering immune responses and contributing to chronic symptoms through cytokine imbalances, T‐cell exhaustion, and systemic inflammation. These symptoms parallel other post‐viral syndromes such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), suggesting similar mechanisms of pathology. The coronavirus has also been linked to neuroinflammation and endothelial dysfunction causing cognitive symptoms and cardiovascular complications. Furthermore, its ability to lower energy production links it to post‐exertion malaise (PEM) and muscle pain. These symptoms may result from iron dysregulation and persistent oxidative stress due to Covid‐impaired mitochondrial function. This review synthesizes current data on the mechanisms that drive Long Covid pathogenesis and explores potential therapeutic strategies to mitigate viral persistence, immune dysfunction, and metabolic disturbances. It is critical to understand these interactions to develop targeted interventions that address the long‐term sequelae of SARS‐CoV‐2 infection and improve patient outcomes.