Abstract. Obesity induces a chronic systemic inflammatory state characterized by impaired adipokine signaling, increased pro-inflammatory cytokine expression, inflammatory cell activation, enhanced generation of oxidizing species and pathogenic shifts in metabolic intermediates and microbial profiles. This impacts pulmonary function and increases the incidence of asthma and its exacerbations that are resistant to conventional asthma therapies. Unsaturated fatty acid nitration products (NO2-FA), generated by metabolic and inflammatory reactions, can orchestrate diverse adaptive signaling responses. When administered as pure synthetic homologs, NO2-FA mediate post-translational protein modifications that modulate activities of multiple enzymes, receptors and transcription factors regulating metabolism and inflammation. Oral administration of synthetic NO2-FA 10-nitro- octadec-9-cis-enoic acid (termed NO2-OA or CXA-10) is a safe, novel pleiotropic drug candidate that is a synthetic homolog of an endogenous mediator. In murine models of metabolic syndrome, obesity-associated allergic airway disease and pulmonary inflammation affirms that CXA-10 induces anti-inflammatory responses and normalizes airway function. We will evaluate the promising pharmacology of this new drug class via Phase 2 evaluation of the therapeutic effects of CXA-10 in subjects with late onset obesity-associated asthma. We will a) define changes in pre bronchodilator FEV1, asthma control, and methacholine responsiveness following daily oral CXA-10 administration to obese subjects (BMI >30) having airway hyperreactivity, via a blinded, placebo- controlled, double cross-over study design and b) evaluate the impact of CXA-10 administration on study subject nasal and pulmonary airway cell gene expression, urine, plasma and bronchoalveolar lavage inflammatory biomarkers and gut-lung axis microbiome responses. These mechanistic studies will reveal how CXA-10 directs the electrophilic NO2-FA-sensitive genome and microbiome to modulate systemic and airway metabolic and inflammatory intermediates that contribute to the obese asthmatic phenotype. We hypothesize that nitro-fatty acid-induced signaling and metabolic responses will improve lung function, asthma control and alleviate obesity-related airway hyperreactivity. To test this hypothesis, Aim #1 evaluates the clinical responses of obesity-associated asthma patients to the orally-administered nitro-fatty acid, CXA-10 and Aim #2 identifies the downstream host and microbial gene expression and metabolic responses of subjects before and after oral CXA-10 administration. Current data encourages that, in the setting of obesity, CXA-10 will limit lung dysfunction, promote adaptive signaling responses and shift gut bacterial populations and metabolic intermediates so as to beneficially impact the gut-lung axis.