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.