TAT-PBX1 fusion protein alleviates LPS-induced acute lung injury via AMPK-TFAM signaling activation.

Acute lung injury (ALI) represents a critical clinical challenge characterized by uncontrolled pulmonary inflammation and disrupted tissue homeostasis, often leading to severe respiratory dysfunction. Current pharmacological interventions and vaccines have demonstrated suboptimal clinical outcomes in modulating disease progression, highlighting the urgent need for innovative therapeutic strategies. A key pathophysiological feature of ALI involves dysregulation of redox homeostasis and excessive pulmonary inflammation. Based on the demonstrated capacity of PBX1 to mitigate reactive oxygen species (ROS)-induced cellular damage, we hypothesized its therapeutic potential for ALI management. Overexpression of PBX1 in A549 cells can alleviate the increase in tumor necrosis factor α, interleukin (IL)-1β, and IL-6 levels caused by lipopolysaccharide (LPS). To circumvent the limitations associated with viral transduction while enabling efficient macromolecular delivery, we engineered a novel TAT-PBX1 fusion protein. In vivo, TAT-PBX1 effectively attenuated LPS-induced ROS accumulation and inflammatory cytokines, while preserving mitochondrial morphology. It restored ATP levels and the NAD(+)/NADH ratio, upregulated PGC-1α/TFAM expression, and suppressed cGAS-STING pathway activation. Mechanistically, TAT-PBX1 targets AMPKγ2 to activate the AMPK-TFAM signaling pathway, exerting anti-inflammatory and lung-protective effects. These findings identify TAT-PBX1 as a promising therapeutic candidate for mitigating pathological responses in ALI.