JAK/STAT Signalling Emerges as Central Player in Post-COVID Autoimmune Syndromes

A new review published in Frontiers in Pharmacology examines how a single cellular signalling circuit, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, may tie together the acute inflammatory storm of COVID-19 and the persistent, debilitating symptoms that linger in many patients long after the virus has cleared. Written by researchers at the University of Perugia, Sapienza University of Rome, Reichman University and the Sheba Medical Center, the review argues that understanding this pathway could clarify why some people develop post-COVID syndrome, also known as Long COVID, and how existing anti-inflammatory drugs might be redirected to treat it. Post-COVID syndrome encompasses a heterogeneous collection of manifestations, including profound fatigue, joint pain, cognitive disturbances and dysautonomia, a dysfunction of the autonomic nervous system.

The review positions the JAK/STAT pathway as a central mediator in the inflammatory cascade triggered by SARS-CoV-2 infection, a signalling route through which many cytokines exert their effects on immune cells. The pathway's role is described as dual. During the acute phase of COVID-19, JAK/STAT signalling contributes to the cytokine storm that characterises severe disease, the runaway production of inflammatory messengers that damages lung tissue and drives systemic illness.

Yet the same signalling machinery may also participate in post-infectious autoimmune phenomena, when the immune system, having been activated by the virus, begins producing autoantibodies or sustaining inflammatory responses in the absence of active infection. A substantial portion of the review is devoted to JAK inhibitors, a class of drugs that blocks the enzymatic activity of Janus kinases and thereby dampens cytokine signalling. The authors summarise the current understanding of these agents as therapeutics for mitigating hyperinflammation during active infection, and they examine the emerging, still preliminary, role of JAK inhibitors in the management of post-COVID syndromes.

The review also addresses a distinctive immunological feature of post-COVID illness: the formation of autoantibodies targeting the autonomic nervous system. By mapping these antibody-mediated disturbances onto the broader cytokine signalling framework, the authors attempt to build a coherent immunopathological model in which JAK/STAT activity sits upstream of both systemic inflammation and organ-specific autonomic dysfunction. Safety considerations receive careful treatment.

The review discusses the safety profile of these drugs and their impact on vaccine immunogenicity, an important practical concern for a patient population in which vaccination status and immune responsiveness remain clinically relevant. As a review article, the work synthesises existing literature rather than reporting new clinical trial data, and its therapeutic discussion should be read as a mapping of current understanding and emerging hypotheses rather than established treatment recommendations. The authors note that the final, formatted version of the article was accepted for publication in the journal's Inflammation Pharmacology section, with correspondence directed to Carlo Perricone of the University of Perugia.

The international author team includes Yehuda Shoenfeld, a prominent figure in autoimmunity research, alongside Fulvia Ceccarelli of Sapienza University and colleagues from the Perugia rheumatology group. The broader significance of the review lies in what it suggests about chronic disease beyond COVID-19. The authors argue that dissecting the immunopathological mechanisms underpinning post-COVID syndrome may not only inform therapeutic strategies for these patients but also illuminate pathways involved in chronic autoimmune conditions more generally.

Subject of Research: The role of the JAK/STAT signalling pathway in post-COVID autoimmune syndromes and JAK inhibitor therapy

Article Title: The role of the JAK/STAT pathway in the pathogenesis and treatment of post-COVID autoimmune syndromes

Article References: Bruno, L., Di Berardino, M., Cafaro, G., Pozzolo, R. D., Ceccarelli, F., Shoenfeld, Y., Gerli, R., Bartoloni, E., & Perricone, C. (2026). The role of the JAK/STAT pathway in the pathogenesis and treatment of post-COVID autoimmune syndromes. Frontiers in Pharmacology, 17, Article 1939700. https://doi.org/10.3389/fphar.2026.1939700

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DOI: 10.3389/fphar.2026.1939700

Keywords: Long COVID, JAK/STAT pathway, JAK inhibitors, autoimmune diseases, cytokine storm, dysautonomia, fibromyalgia, chronic fatigue syndrome, SARS-CoV-2, autoantibodies, inflammation, immunotherapy