Baliosperoid A attenuates lipopolysaccharide-induced acute lung injury by targeting SHP2 to inhibit inflammation and oxidative stress.

Acute lung injury (ALI) remains a devastating clinical condition with limited therapeutic options. While Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2) has emerged as a critical mediator in ALI pathogenesis, effective SHP2-targeting therapeutics remain largely elusive. Baliospermum solanifolium (Burm.) is a traditional medicine used to treat various diseases such as asthma, edema, bronchitis, jaundice, and constipation. Baliosperoid A (BA), a diterpenoid compound derived from Baliospermum solanifolium's roots, exhibits potent NO inhibitory activity in RAW264.7 cells. However, its anti-inflammatory activity and potential targets have never been reported. Here, we report BA acts as a selective SHP2 inhibitor with remarkable therapeutic potential against ALI. Through comprehensive molecular and functional analyses, we demonstrate that BA directly binds to and inhibits SHP2 phosphatase activity with high specificity (IC₅₀ = 1.638 ± 0.324 μM). Mechanistically, BA orchestrates a dual-action therapeutic effect by simultaneously suppressing inflammatory cascades through SHP2-mediated MAPK and NF-κB pathway inhibition while activating the Nrf2-dependent antioxidant response. In preclinical models of ALI and sepsis, BA treatment significantly improved survival rates, preserved lung architecture, and prevented multi-organ dysfunction. Notably, BA demonstrated superior efficacy to the existing SHP2 inhibitor SHP099, particularly in sepsis survival outcomes (90 % vs 50 % survival at 24 h). Our findings not only identify BA as a promising therapeutic candidate for ALI but also establish a novel paradigm for targeting SHP2 in inflammatory diseases.