Thirty days of supplementation with PQQ reprograms immunometabolic networks in Western diet-fed female baboons

ABSTRACT Western-style diets promote chronic metabolic inflammation and dyslipidemia, yet safe interventions that restore immunometabolic homeostasis remain limited. Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor with antioxidant and metabolic regulatory properties, but its systemic effects in translational preclinical models are poorly defined. Here, we examined the impact of short-term PQQ supplementation in obese adult female olive baboons (Papio anubis) chronically fed a Western diet. Using a human-equivalent dose administered for 30 days, we found that PQQ supplementation significantly reduced circulating markers of systemic inflammation and cholesterol in Western-diet-fed animals, lowering circulating C-reactive protein, soluble CD163, and atherogenic lipoprotein fractions independent of changes in adiposity. Proteomic and pathway analyses of circulating proteins in plasma and serum revealed suppression of complement, thrombo-inflammatory, and extracellular matrix remodeling pathways, alongside enhanced lipoprotein assembly, remodeling, and clearance. Network analyses identified restoration of neurotrophic tyrosine kinase receptor 1 (NTRK1)- and forkhead box A2 (FOXA2)-regulated signaling as central features of the PQQ response, accompanied by inhibition of pro-fibrotic, xenobiotic, and inflammatory pathways, as well as predicted activation of liver X receptor (LXR)- and insulin growth factor (IGF)-associated metabolic programs. These findings demonstrate that PQQ rapidly reprograms systemic immunometabolic networks in a nonhuman primate model of diet-induced metabolic stress, highlighting FOXA2- and neurotrophin-associated pathways as novel targets of PQQ’s action. Competing Interest Statement The authors have declared no competing interest. Footnotes Grant support: This research was funded by in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK 139443 to KRJ and DAM and by the Presbyterian Health Foundation in the form of a Bridge Grant awarded to KRJ. DATA AVAILABILITY The mass spectrometry proteomics data generated in this study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD072309 and 10.6019/PXD072309. All other data generated in this study are provided in the Supplementary Information.