Cannabichromeorcin targets cathepsin L to alleviate oxidative stress-Driven airway inflammation in severe asthma

<h4>Background</h4>Severe asthma (SA) is characterized by corticosteroid insensitivity, persistent airway inflammation, and excessive oxidative stress, underscoring an urgent unmet therapeutic need. Meroterpenoids derived from Rhododendron capitatum Maxim have demonstrated potent anti-inflammatory properties; however, their therapeutic potential in SA has not been elucidated.<h4>Methods</h4>A meroterpenoid-rich fraction was isolated from R. capitatum Maxim, and cannabichromeorcin (CBCO) was identified as its most abundant constituent. The therapeutic effects of CBCO were evaluated in murine models of SA induced by toluene diisocyanate or by combined house dust mite and lipopolysaccharide exposure. Transcriptomic profiling, TargetNet-based target prediction, molecular docking, and molecular dynamics simulations were employed to identify pharmacological targets. Clinical relevance was examined using transcriptomic datasets from the Unbiased BIOmarkers in Prediction of REspiratory Disease Outcomes project (U-BIOPRED) and validated in an independent clinical cohort.<h4>Results</h4>Pretreatment with CBCO ameliorated airway inflammation and oxidative stress in murine models of SA. An integrative approach identified cathepsin L (CTSL) as a redox-sensitive pharmacological target of CBCO. Pretreatment with CBCO inhibited CTSL, thereby reducing the formation of neutrophil extracellular traps containing MMP8, and attenuating the activation of the unfolded protein response (UPR). Pharmacological inhibition of CTSL, MMP8, or the UPR recapitulated the protective effects of CBCO. In vitro, CBCO preserved airway epithelial barrier integrity, reduced reactive oxygen species accumulation, and suppressed alarmin release. Clinically, transcriptomic analyses from the U-BIOPRED cohort revealed elevated MMP8 and DDIT3 expression in sputum and blood samples from patients with SA. In our independent validation cohort, serum MMP8 and DDIT3 levels were increased in SA. Receiver operating characteristic analyses confirmed serum MMP8 and DDIT3 as predictive biomarkers for SA.<h4>Conclusion</h4>CBCO conferred protection against the development of SA by targeting CTSL to suppress NET formation, UPR activation, and downstream oxidative stress. MMP8 and DDIT3 emerged as promising biomarkers for predicting disease severity.