Taming the Cytokine Storm: Therapeutic Strategies for Post‐Acute Sequelae of SARS‐CoV‐2 Infection

ABSTRACT Background and Aim Post‐acute sequelae of SARS‐CoV‐2 infection (PASC), commonly referred to as long COVID, has emerged as a significant global health concern, marked by persistent symptoms and chronic inflammation following recovery from acute COVID‐19. A central driver of PASC pathogenesis is the sustained cytokine storm—an exaggerated and prolonged pro‐inflammatory response that leads to ongoing tissue injury and multisystem dysfunction. This review aims to synthesize current knowledge on cytokine dysregulation in PASC and evaluate emerging therapeutic strategies targeting these immunopathological mechanisms. Methods A narrative review methodology was employed, drawing from recent peer‐reviewed publications, clinical trial databases, and immunological studies published between 2020 and 2025. Articles focusing on cytokine profiles in PASC, immune reprogramming, and immunomodulatory therapies were included. Mechanistic studies, biomarker research, and translational trials involving corticosteroids, cytokine inhibitors, Janus kinase (JAK) inhibitors, and novel biologics were critically analyzed. Results The literature reveals that elevated levels of IL‐6, IL‐1β, TNF‐α, and IFN‐γ persist in a subset of PASC patients, contributing to chronic systemic and organ‐specific inflammation. Emerging therapies—including IL‐6 and IL‐1 receptor antagonists, JAK inhibitors, and CNS‐penetrant anti‐inflammatory agents—demonstrate promise in modulating cytokine storms and improving clinical outcomes. Recent insights into cytokine profiling, trained immunity, and neuroimmune crosstalk suggest potential for precision‐based interventions tailored to distinct inflammatory phenotypes in PASC. Conclusion Persistent cytokine dysregulation underlies the pathophysiology of PASC and offers actionable targets for therapeutic intervention. Immunomodulatory strategies, when guided by biomarker profiling and systems biology approaches, hold promise for mitigating long‐term complications of COVID‐19. Future research should prioritize personalized treatment algorithms to address the heterogeneity of PASC and enhance patient recovery.