Nitric oxide redox signaling as a convergent mechanism in aging and fibrosis.

Nitric oxide (NO) is a pleiotropic gaseous mediator that regulates tissue homeostasis. At physiological levels, it functions as a precise signaling molecule through soluble guanylate cyclase (sGC) activation and the reversible S-nitrosylation of cysteine residues. However, in the context of aging and fibrosis, oxidative stress disrupts this balance. The increased generation of superoxide (O₂•⁻) anions diverts NO from homeostatic signaling to form peroxynitrite (ONOO⁻), a potent oxidant. This biochemical transition drives cellular dysfunction by promoting the senescence(definition)-associated secretory phenotype (SASP), dysregulating nutrient sensing pathways including the PI3K-Akt-PTEN and AMPK-mTOR(definition), and disrupting proteostasis(definition). Moreover, this redox dysregulation perpetuates fibrosis by inducing myofibroblast differentiation and altering extracellular matrix stability via matrix metalloproteinases. This review delineates the NO-redox axis as a convergent mechanism linking the aging-fibrosis synergy. It highlights how the shift from protective S-nitrosylation to pathological protein nitration locks tissues in a dysfunctional state. Finally, therapeutic strategies targeting this axis are explored, emphasizing the limitations of non-selective antioxidants. Consequently, emphasis is placed on precision redox pharmacology approaches that integrate selective peroxynitrite scavengers and endothelial nitric oxide synthase recoupling agents with metabolic modulators including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. This framework provides new perspectives for the development of targeted interventions against aging-related fibrotic diseases.