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Review
. 2025 Sep;29(5):617-636.
doi: 10.1007/s40291-025-00792-8. Epub 2025 Jun 18.

Advances in Understanding Long COVID: Pathophysiological Mechanisms and the Role of Omics Technologies in Biomarker Identification

Mônica Duarte da Silva  1   2 , Thamires Santos da Silva  2 , Claudemir Gregório Mendes  3 , Maria Carolina Miglino Valbão  3 , Abraham Kwame Badu-Tawiah  1 , Lucas Fornari Laurindo  3   4 , Sandra Maria Barbalho  3   4 , Rosa Direito  5 , Maria Angélica Miglino  4   6   7
Affiliations
Review

Advances in Understanding Long COVID: Pathophysiological Mechanisms and the Role of Omics Technologies in Biomarker Identification

Mônica Duarte da Silva et al. Mol Diagn Ther. 2025 Sep.

Abstract

Long coronavirus disease (COVID) is a multisystem condition that affects a significant proportion of individuals following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with persistent symptoms ranging from fatigue and cognitive dysfunction to cardiovascular disorders. It is estimated that 30-60% of infected individuals experience symptoms lasting more than 12 weeks. Despite advances in understanding acute infection, the pathophysiological mechanisms underlying long COVID remain unclear. Current hypotheses suggest that viral persistence, immune dysfunction, and metabolic alterations play central roles. Omics approaches, including metabolomics, proteomics, and lipidomics, have played a crucial role in investigating molecular changes, identifying biomarkers, and refining therapeutic strategies. This review discusses recent advances in understanding long COVID, addressing its mechanisms, risk factors, the impact of viral variants, and the role of vaccination, with an emphasis on the importance of omics technologies in elucidating this condition.

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Conflict of interest statement

Declarations. Conflict of interest: The authors (M.D.d.S., T.S.d.S., C.G.M., M.C.M.V., A.K.B.T., L.F.L., S.M.B., R.D., and M.A.M) declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author contributions: Conceptualization, M.D.d.S., T.S.d.S., C.G.M., M.C.M.V., A.K.B.T., L.F.L., S.M.B., R.D., and M.A.M.; methodology, M.D.d.S., T.S.d.S., C.G.M., M.C.M.V., A.K.B.T., L.F.L., S.M.B., R.D., and M.A.M.; writing—original draft preparation, M.D.d.S., T.S.d.S., C.G.M., M.C.M.V., A.K.B.T., L.F.L., S.M.B., R.D. and M.A.M.; writing—review and editing, M.D.d.S., T.S.d.S., C.G.M., M.C.M.V., A.K.B.T., L.F.L., S.M.B., R.D., and M.A.M. All authors have read and agreed to the published version of the manuscript. Funding: Open access funding provided by FCT|FCCN (b-on). This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Process No. 200177/2022-2). Ethics approval: Not applicable. Consent (participation and publication): Not applicable. Data availability: Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study. Code availability: Not applicable.

Figures

Fig. 1
Fig. 1
Following exposure to SARS-CoV-2, individuals may develop symptoms during the acute phase, which typically spans up to 4 weeks from symptom onset and is characterized by high viral load. The post-acute phase occurs between weeks 4 and 12, during which ongoing or relapsing symptoms may persist despite viral clearance. Symptoms that continue or emerge from week 12 onwards are classified as long COVID, reflecting prolonged or new-onset complications beyond the initial infection. Created using BioRender.com
Fig. 2
Fig. 2
Pathophysiological mechanisms of long COVID. Scheme of mechanisms contributing to long COVID, including the persistence of a viral reservoir and autoimmunity. The resulting consequences include a cytokine storm, organ damage, chronic inflammation, and an altered immune status, which collectively contribute to the prolonged symptoms observed in long COVID. These factors lead to systemic effects, including endothelial dysfunction, microbiome dysbiosis, mitochondrial dysfunction, metabolic dysregulation, and dysregulation of genes involved in tissue repair and regeneration. Created using BioRender.com
See this image and copyright information in PMC

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