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RUNX2 and USP16 Regulate MFRN2 Stability via Deubiquitination to Maintain Pulmonary Epithelial Barrier Integrity in sepsis-induced ALI

ABSTRACT: Sepsis is a life-threatening condition characterized by high morbidity and mortality, with acute lung injury (ALI) being one of its most common and severe complications. However, the precise molecular mechanisms underlying ALI remain unclear. Here, we identify RUNX2 as a critical mediator of epithelial injury in sepsis-induced ALI, independent of macrophage activation. Mechanistically, lipopolysaccharide (LPS) stimulation enhances the binding of RUNX2 to the USP16 promoter, thereby transcriptionally activating USP16 expression. This activation reduces K27-linked ubiquitin chains on MFRN2 at lysine 97, leading to mitochondrial iron dyshomeostasis and promoting epithelial ferroptosis. Moreover, AHR interacts with RUNX2 to suppress its activation, thereby attenuating epithelial apoptosis. Collectively, our study uncovers a previously unrecognized mechanism by which LPS triggers epithelial cell death in ALI and suggests that targeting RUNX2 transcriptional activation may enhance epithelial resistance injury induced by sepsis.

ORGANISM(S): Mus Musculus

SUBMITTER: Wanli Jiang

PROVIDER: PXD074209 | iProX | Sat Feb 07 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

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RUNX2 and USP16 Regulate MFRN2 Stability via Deubiquitination to Maintain Pulmonary Epithelial Barrier Integrity in sepsis-induced ALI

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