Karacoline attenuates sepsis-induced acute lung injury by suppressing apoptosis via PPARγ-associated inhibition of JNK/ERK MAPK signaling

Background: Sepsis-induced acute lung injury (SALI) is a fatal complication of sepsis with limited therapeutic options. Karacoline, a diterpenoid alkaloid from Aconitum, shows potential protective effects, but its mechanism in SALI remains unclear.

Methods: Network pharmacology and WGCNA identified core targets and pathways of Karacoline, with molecular docking confirming its binding to PPARγ. A cecal ligation and puncture mouse model was used to assess lung pathology, edema, barrier dysfunction, inflammatory cytokines, and Apoptosis. In vitro, LPS-stimulated MH-S cells were used to evaluate Apoptosis, ROS generation, mitochondrial function, and PPARγ/MAPK signaling. The PPARγ Antagonist GW9662 was used to verify the involvement of PPARγ in the protective effects of Karacoline.

Results: Karacoline significantly alleviated lung injury, reduced the W/D ratio, decreased total protein and albumin levels in BALF, and suppressed IL-1β, IL-6, and TNF-α. Mechanistically, Karacoline upregulated PPARγ expression and inhibited ERK1/2 and JNK phosphorylation, thereby contributing to the reduction of pulmonary cell Apoptosis. In vitro, Karacoline limited ROS generation, maintained mitochondrial membrane potential, and reduced LPS-induced Apoptosis in MH-S cells. Moreover, GW9662 weakened the anti-apoptotic effect of Karacoline and partially reversed its inhibition of JNK/ERK activation, further supporting the involvement of PPARγ in Karacoline-mediated inhibition of JNK/ERK MAPK signaling and Apoptosis.

Conclusion: Karacoline protects against SALI by suppressing mitochondrial Apoptosis, an effect closely associated with PPARγ-related inhibition of JNK/ERK MAPK signaling. These findings suggest that Karacoline may be a candidate compound worthy of further validation for sepsis-induced lung injury intervention.