Asthma is a complex inflammatory disease where oxidative stress and immune metabolic dysfunction coexist. As master regulators of this interface, macroautophagy/autophagy and nitric oxide (NO) signaling govern immune polarization, metabolic flux, and mitochondrial integrity. While NO functions as a redox messenger that affects both protective and pathogenic outcomes, autophagy maintains cellular homeostasis through coordinated degradation and recycling processes. These pathways come together to form a regulatory triad that controls T-cell differentiation, macrophage activation, and airway remodeling. Here, we outline the ways in which autophagy-NO interactions alter immune metabolism to fuel inflammation in asthma and investigate their potential as a combined therapeutic target. We offer a systems-level perspective of immune reprogramming by mapping important molecular nodes, including those involving MTOR, AMPK, BECN1, NOS2/iNOS, and NOS3/eNOS, and connecting them to metabolic checkpoints. Finally, as a potential avenue that can offer improved efficacy and durability in the management of asthma, we highlight translational strategies that combine autophagy modulators, NO donors or inhibitors, and metabolic regulators.Abbreviations: ASM: airway smooth muscle; COPD: chronic obstructive pulmonary disease; DC: dendritic cell; FAO: fatty acid oxidation; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; L-NIL: L-N6-(1-Iminoethyl)lysine (selective NOS2 inhibitor); M1 and M2: macrophage pro-inflammatory and anti-inflammatory polarization states; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2; NOS3/eNOS: nitric oxide synthase 3; OXPHOS: oxidative phosphorylation; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; ROS: reactive oxygen species; TGFB1/TGF-β1: transforming growth factor beta 1; Treg: regulatory T cell; TSLP: thymic stromal lymphopoietin.
