Inflammation-driven mitochondrial dysfunction and ROS accumulation orchestrate pulmonary fibrotic remodeling in sepsis.

Inflammation-induced pulmonary fibrosis is an irreversible and severe complication that leads to persistent decline in lung function and increased mortality; however, its early pathogenesis is still unclear. This study aimed to systematically elucidate the initiation mechanism of pulmonary fibrosis in the early stages of inflammation. By integrating multi-omics data and animal models, we found that lung exhibits stronger immune amplification and more severe mitochondrial dysfunction in comparison with other organs during inflammation, consequently fibrotic signaling is initiated in the acute phase. Mitochondria-related gene analysis identified six key genes (Bcl2l1, Gsr, Msrb3, AA467197, Stom, and Sod2) involved in the regulation of reactive oxygen species (ROS) metabolism, which were closely associated with clinical outcomes in sepsis. Temporal data and TNF-α/IL-1β intervention experiments revealed that these cytokines are persistently overexpressed in septic lungs, serving as critical drivers of ROS activation. In vitro assays further confirmed that ROS overload directly induces cellular damage and functional reprogramming of fibroblasts. Through bulk and single-cell transcriptomic analyses, we elucidated the alteration of intercellular communication between immune and parenchymal cells, and identified Col13a1+ fibroblasts as a key subpopulation with the capability to drive fibrotic remodeling. In conclusion, sustained TNF-α/IL-1β signaling in septic lungs exacerbates ROS accumulation, thereby driving aberrant fibroblast repair and initiating pulmonary fibrosis, in which Col13a1+ fibroblasts represent the major profibrotic subpopulation. Thus, the early inhibition of TNF-α/IL-1β expression, suppression of ROS accumulation, and regulation of Col13a1+ fibroblast activation may provide an effective therapeutic strategy for sepsis.