Breaking a mitochondrial danger-STING feed-forward amplifier preserves alveolar-capillary architecture and dampens interferon-chemokine signaling in acute lung injury.

Acute lung injury (ALI) is defined by disruption of alveolar-capillary architecture, inflammatory remodeling of the parenchyma, and barrier dysfunction. Mitochondrial structural damage can promote release of mitochondrial danger signals that engage cytosolic DNA sensing and amplify tissue injury. Here, we tested whether dual targeting of mitochondrial structure-function (elamipretide, ELM) and STING signaling (H151) preserves lung tissue organization. At 24 h post intratracheal lipopolysaccharide, lung architecture was assessed histologically, and BALF and lung tissue were analyzed for barrier and cytolytic injury (BALF protein, LDH, NOx), inflammatory cellularity and effector activity (BALF leukocytes/neutrophils, MPO), oxidative stress and antioxidant defenses (ROS, malondialdehyde, glutathione, SOD), mitochondrial leak (cytosolic mtDNA, TFAM), and cGAS-STING pathway activation (phospho-STING/TBK1/IRF3) with downstream interferon-chemokine output (IFN-β, IFN-α, CXCL10, CCL5) and NFκB-driven cytokines (IL-1β, TNF-α, IL-6). LPS caused marked histologically compromised alveolar structure, accompanied by redox imbalance, mitochondrial leak, activation of cGAS-STING signaling, induction of interferon-chemokine programs, increased barrier permeability, and neutrophilic alveolitis. ELM predominantly improved redox status and reduced mitochondrial leak, while H151 primarily suppressed STING target engagement and interferon-chemokine induction. Notably, combined ELM+H151 produced the most comprehensive protection, yielding the greatest improvement in lung histology together with reductions in barrier disruption, inflammatory cellular infiltration, and downstream signaling outputs. Integrated analyses linked mitochondrial leak markers to signaling and injury indices and supported system-level recovery toward control with combination treatment. Collectively, these findings indicate that interrupting a mitochondrial danger-STING feed-forward axis is associated with preservation of alveolar-capillary architecture in experimental ALI.