Reprogramming NAD

Abstract

Pulmonary fibrosis arises from intertwined oxidative, inflammatory, and profibrotic processes, whereas current therapies target only parts of this network. Here, we evaluated an adjunctive strategy in which nicotinic acid (NA), a NAD+-supporting supplement/adjuvant, was added to semaglutide (SEMA), a GLP-1 receptor agonist. The prespecified objective was to determine whether adding NA to SEMA provides greater protection than SEMA alone in bleomycin (BLM)-induced pulmonary fibrosis. Rats were challenged with BLM and treated with SEMA, NA, or SEMA+NA for 21 days. Biochemical, molecular, histological, and western blot endpoints were assessed, and the fixed-dose Highest Single Agent (HSA) and Bliss independence models were used as exploratory interaction metrics. BLM induced oxidative stress, inflammatory cytokine elevation, NAD+ and SIRT1 depletion, FOXO3a suppression, TGF-β/SMAD activation, and collagen deposition. Compared with SEMA alone, SEMA+NA produced broader protection, restoring NAD+/SIRT1-FOXO3a-Nrf2 pathway-associated readouts and suppressing NF-κB/TGF-β-linked inflammatory and fibrotic markers. Exploratory HSA and Bliss analyses suggested enhanced fixed-dose effects across several endpoints but were interpreted descriptively, not as definitive pharmacological synergy. These findings indicate that NA-driven NAD+ metabolic support can amplify the protective profile of SEMA in experimental pulmonary fibrosis. Dose-response matrices, pathway-inhibition studies, temporal profiling, and lung-function testing remain required to establish definitive synergy, mechanism, and translational relevance.

Key Findings

• Bleomycin-induced pulmonary fibrosis is characterized by oxidative stress, inflammatory cytokine elevation, NAD+ and SIRT1 depletion, FOXO3a suppression, TGF-β/SMAD activation, and collagen deposition.
• Combination treatment with nicotinic acid (NA) and semaglutide (SEMA) restored NAD+/SIRT1-FOXO3a-Nrf2 pathway activity and suppressed NF-κB/TGF-β-linked inflammatory and fibrotic markers more effectively than SEMA alone.
• Exploratory interaction models suggested enhanced protective effects of the NA and SEMA combination, though definitive pharmacological synergy requires further investigation.

Clinical Significance

Citation

Mo'men Maha, Saber Sameh, Amer Ahmed Eet al.. Reprogramming NAD Toxicology and applied pharmacology. 2026-Sep-19.