Frontiers in immunology · 2026
Targeting the ISG15+STAT1+ monocyte-driven inflammatory storm with Fedratinib in traumatic lung injury via the JAK2/STAT3/PIM1 axis.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Kun, Li Dan, Gao Le, Chen Mingwei
Аннотация
BACKGROUND: Traumatic lung injury (TLI) frequently progresses to acute respiratory distress syndrome (ARDS), a condition with high mortality and limited targeted therapies. This study aimed to identify specific immune cell drivers and potential therapeutic targets for precision intervention in TLI.
METHODS: We conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells of trauma patients, transcriptomic data from alveolar macrophages in ARDS patients, and lung tissue transcriptomic data from a TLI mouse model. An integrated bioinformatics approach was employed, including the use of the Augur and Milo algorithms for prioritizing cellular perturbations, Monocle 3 for trajectory inference, and two-sample Mendelian randomization (TSMR) for causal inference. Potential drugs were screened using Connectivity Map, target-specificity predictions were made using the scRANK algorithm, and validation was performed using an in vitro macrophage polarization model.
RESULTS: The scRNA-seq analyses revealed that classical monocytes showed the greatest disturbance and response following trauma. Among these, the ISG15+STAT1+ monocyte subpopulation expanded post-trauma and drove an inflammatory storm through robust M1-like polarization. PIM1 was identified as a core pathogenic gene co-upregulated in both peripheral blood and lung tissue. Further TSMR analysis confirmed elevated PIM1 expression as a causal risk factor for ARDS. Concurrently, the JAK2/STAT3/PIM1 pathway is activated synchronously during the acute trauma phase. Drug repurposing research suggests that the JAK2 inhibitor Fedratinib can reverse the transcriptomic characteristics of TLI. In vitro experiments have demonstrated that Fedratinib effectively inhibits M1 polarization and the expression of inflammatory genes by interfering with the JAK2/STAT3/PIM1 signaling axis.
CONCLUSIONS: This study identifies the JAK2/STAT3/PIM1 signaling axis within the ISG15+STAT1+ monocyte subpopulation as a key driver of TLI and a potential therapeutic target, and suggests that fedratinib is a potential candidate for the targeted treatment of TLI.
METHODS: We conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells of trauma patients, transcriptomic data from alveolar macrophages in ARDS patients, and lung tissue transcriptomic data from a TLI mouse model. An integrated bioinformatics approach was employed, including the use of the Augur and Milo algorithms for prioritizing cellular perturbations, Monocle 3 for trajectory inference, and two-sample Mendelian randomization (TSMR) for causal inference. Potential drugs were screened using Connectivity Map, target-specificity predictions were made using the scRANK algorithm, and validation was performed using an in vitro macrophage polarization model.
RESULTS: The scRNA-seq analyses revealed that classical monocytes showed the greatest disturbance and response following trauma. Among these, the ISG15+STAT1+ monocyte subpopulation expanded post-trauma and drove an inflammatory storm through robust M1-like polarization. PIM1 was identified as a core pathogenic gene co-upregulated in both peripheral blood and lung tissue. Further TSMR analysis confirmed elevated PIM1 expression as a causal risk factor for ARDS. Concurrently, the JAK2/STAT3/PIM1 pathway is activated synchronously during the acute trauma phase. Drug repurposing research suggests that the JAK2 inhibitor Fedratinib can reverse the transcriptomic characteristics of TLI. In vitro experiments have demonstrated that Fedratinib effectively inhibits M1 polarization and the expression of inflammatory genes by interfering with the JAK2/STAT3/PIM1 signaling axis.
CONCLUSIONS: This study identifies the JAK2/STAT3/PIM1 signaling axis within the ISG15+STAT1+ monocyte subpopulation as a key driver of TLI and a potential therapeutic target, and suggests that fedratinib is a potential candidate for the targeted treatment of TLI.