Proteasome subunit-based biomarker panel for early diagnosis of acute respiratory distress syndrome and therapeutic targeting of PSMB8 in a mouse model

Acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in intensive care units worldwide. Timely diagnosis and targeted treatment are critical for significantly improving patient outcomes. Plasma proteomics from 196 patients with ARDS, 100 non-ARDS pulmonary patients, and 100 healthy controls were analyzed to construct a LASSO regression-based diagnostic model. Biomarker origins and therapeutic targets were further investigated using clinical bronchoalveolar lavage fluid (BALF) and a lipopolysaccharide-induced mouse model of ARDS. Proteasome-related pathways were significantly activated in ARDS. A 7-immunoproteasome subunit panel demonstrated robust diagnostic accuracy for ARDS in both the training ( n = 277, AUC 0.908) and independent validation cohorts ( n = 119, AUC 0.890). In the mouse model, PSMB8 expression was upregulated in lung tissues, primarily sourced from monocytes or macrophages, and correlated with disease severity. Pharmacological inhibition of PSMB8 or genetic deletion of Psmb8 attenuated lung injury, inflammation, and respiratory dysfunction. Mechanistically, PSMB8 deficiency suppressed M1-like macrophage polarization, consistent with altered lipid metabolic pathways. Collectively, this study provides a combined clinical strategy of using the 7-subunit proteasome panel for ARDS diagnosis. Furthermore, targeting PSMB8 to modulate inflammatory macrophage responses defines it as a promising but still preclinically validated therapeutic target for ARDS management that warrants further investigation.