Targeting Kynurenine Synthesis Attenuated Cigarette Smoke-Induced COPD-Like Lung Injury Driven by TALDO1-Mediated Metabolic Reprogramming.

Abstract

Chronic obstructive pulmonary disease (COPD) is a devastating condition characterized by airflow limitation, inflammation, and structural lung damage. Metabolic dysregulation is recognized as a critical feature, but the key metabolic drivers remain unclear. This study identifies transaldolase1 (TALDO1) as a previously unrecognized metabolic regulator in cigarette smoke (CS)-induced COPD pathogenesis. TALDO1 is markedly upregulated in airway epithelial cells by CS exposure. Elevated TALDO1 promotes mitochondrial dysfunction, whereas its genetic knockdown attenuates CS-induced lung function decline and pulmonary inflammation. Mechanistically, TALDO1 activation redirects tryptophan metabolism toward the kynurenine pathway, leading to L-kynurenine accumulation. Genetic or pharmacological inhibition of this pathway significantly alleviates mitochondrial damage, while L-kynurenine supplementation exacerbates injury. Treatment with the IDO inhibitor Epacadostat ameliorates CS-induced lung impairment and inflammation in vivo. These findings define a TALDO1-kynurenine-mitochondrial injury axis linking airway epithelial metabolic reprogramming to COPD, providing translational evidence for targeting this pathway as a therapeutic strategy.

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