Respiratory research · 2026
Karacoline attenuates sepsis-induced acute lung injury by suppressing apoptosis via PPARγ-associated inhibition of JNK/ERK MAPK signaling.
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Lei Zihan, He Yuhong, Wang Yuxuan, Yuan Min, Chen Xue, Qin Jingxue, Wu Xiaojing
Аннотация
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.
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.