IL-6/STAT3 signaling drives mitochondrial oxidative phosphorylation dysfunction and AP-1 activation in fibroblasts...

Sepsis-induced acute lung injury (ALI) and early fibrotic remodeling remain major clinical challenges with limited effective treatments. In this study, we systematically investigated the role of fibroblasts in sepsis-associated lung injury and fibrosis using single-cell RNA sequencing combined with functional validation. We found that fibroblast states shifted from a resting state toward pro-inflammatory and pro-fibrotic phenotypes during sepsis, including Glycoprotein-producing Fibroblasts, Stress-activated Fibroblasts, and Inflammatory Fibroblasts, accompanied by increased IL-6 signaling activity. Mechanistically, IL-6/Signal Transducer and Activator of Transcription 3 (STAT3) signaling was associated with impaired mitochondrial oxidative phosphorylation (OXPHOS) in fibroblasts, increased mitochondrial ROS production, and increased activation of the AP-1 transcription factor family, which was linked to enhanced profibrotic protein expression. Pharmacological intervention with clinically relevant glucocorticoids, dexamethasone and methylprednisolone, attenuated lung injury and fibrosis in experimental sepsis-associated lung injury and was associated with suppression of the IL-6/STAT3/OXPHOS/AP-1 axis. Collectively, these findings highlight IL-6/STAT3-mediated mitochondrial metabolic remodeling in fibroblasts as a potential therapeutic target for sepsis-induced lung injury and fibrosis.