Abstract
BACKGROUND: Post-COVID-19 syndrome (PCS) affects around 10% of individuals who experience SARS-CoV-2 infection worldwide. This four-year follow-up study investigated the long-term impact of mesenchymal stromal cell (MSC) therapy on both the occurrence of PCS and its underlying mechanisms. METHODS: We enrolled 148 survivors of severe COVID-19 (92 who received MSC therapy and 56 who served as controls). The clinical evaluations included safety (new-onset comorbidities, oncogenic risk) and efficacy outcomes (computed tomography [CT] imaging, functional capacity, pulmonary function, 36-Item Short-Form Survey [SF-36], PCS prevalence). Serum proteomic profiling was performed to identify the differentially expressed proteins (DEPs) across the PCS subtypes, including chronic fatigue-like syndrome (CFs), respiratory syndrome (REs), chronic pain syndrome (CPs), and neurosensorial syndrome (NSs). RESULTS: MSC therapy had a favorable long-term safety profile. The overall prevalence of PCS was 73.6% (109/148), with CFs being the most common subtype (50.7%, 75/148). Moreover, the incidence of CFs was significantly lower in the MSC group than in the control group (41.3% vs. 66.1%; odds ratio = 0.361, p = 0.003). MSC therapy was also associated with a significant improvement in the SF-36 Role-Emotional domain. No significant differences were observed in the participants’ CT outcomes, functional capacity, or pulmonary function. A predictive model integrating proteomic and clinical data for CFs achieved an area under the curve of 0.773. Unsupervised clustering identified three molecular endotypes, with one being both highly enriched for respiratory syndrome and characterized by dysregulated immune pathways. CONCLUSION: This 4-year follow-up shows a sustained association between MSC therapy and a lower likelihood of CFs in severe COVID-19 survivors, with a favorable safety profile. Integrated proteomic and clinical analysis reveals distinct biological pathways underpinning PCS heterogeneity, suggesting potential biological bases underlying the subtype-specific associations observed with MSC therapy and highlighting potential targets for future precision medicine approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07902-y.