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Volume 18
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Article

Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics

by
Dario Cavaterra
1,
Sara Giammaria
2,
Irene Pandino
2,
Gabriele Antonio Zingale
2,
Valerio Delli Paoli
1,
Rebecca Fiore
3,
Manuele Michelessi
2,
Gloria Roberti
2,
Carmela Carnevale
2,
Lucia Tanga
2,
Daniela Cazzato
1,
Elisa Peroni
4,
Giuseppe Grasso
5,
Gianluca Manni
2,3,
Alessio Bocedi
1,
Francesco Oddone
2,
Massimiliano Coletta
2,
Diego Sbardella
2 and
Grazia Raffaella Tundo
2,3,*
1
Department of Chemical Sciences and Technologies, University of Tor Vergata, 00133 Rome, Italy
2
IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy
3
Department of Clinical Sciences and Translational Medicine, University of Tor Vergata, 00133 Rome, Italy
4
CY Cergy Paris Universitè, CNRS, BioCIS UMR 8076, 95000 Cergy Pointoise, France
5
Department of Chemical Sciences, University of Catania, 95125 Catania, Italy
*
Author to whom correspondence should be addressed.
Pharmaceutics 2026, 18(1), 61; https://doi.org/10.3390/pharmaceutics18010061
Submission received: 18 September 2025 / Revised: 12 December 2025 / Accepted: 24 December 2025 / Published: 1 January 2026
(This article belongs to the Special Issue Advances in Drug Delivery Systems for Targeted Neurological Therapies)
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Abstract

Background/Objectives: Citicoline, also known as CDP-choline, is a nootropic agent currently used in the treatment of glaucoma and is undergoing evaluation as a first-line therapy in a multi-center, international, phase III, randomized clinical trial involving citicoline eyedrops (ClinicalTrials.gov ID: NCT05710198). Numerous clinical and preclinical studies have linked the neuroenhancement and neuroprotective effects of citicoline to its role as a metabolic precursor for structural and functional components of cell membranes (such as phosphatidylcholine and sphingomyelin) and for neurotransmitters (e.g., acetylcholine and dopamine). However, compelling evidence suggests that the molecular mechanisms underlying its cytoprotective activity involve additional as-yet uncharacterized pharmacological actions. Methods: To further elucidate its pharmacology, we investigated the effect of two cytoprotective doses of citicoline (0.1 mM and 1 mM) on the global proteome of neuroblastoma cells using an unbiased shotgun proteomics approach. Results: With over 4000 unique proteins identified and quantified per experimental condition, the proteomics analysis revealed that citicoline, after 6 h of stimulation, induces a profound and robust remodeling of the intracellular proteome compared to untreated cells. Importantly, this effect was observed to significantly diminish by 18 h of stimulation, highlighting its transient nature (data are available via ProteomeXchange with identifier PXD061053). The clustering and rationalization of proteins upregulated by citicoline treatment identified the enrichment of key pathways for mRNA splicing, protein translation, proteostasis balance through the ubiquitin proteasome system (UPS), and mitochondrial metabolism. Conclusions: These proteomics findings introduce previously uncharacterized biological effects of citicoline and foster the working hypothesis that this drug may exert its cytoprotective activity through molecular mechanisms linked to the hormesis principle. These data further support the rationale for its clinical application in neurodegenerative processes and human disorders characterized by proteotoxicity.
Keywords: citicoline; glaucoma; proteomics; proteostasis; proteasome citicoline; glaucoma; proteomics; proteostasis; proteasome

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MDPI and ACS Style

Cavaterra, D.; Giammaria, S.; Pandino, I.; Zingale, G.A.; Delli Paoli, V.; Fiore, R.; Michelessi, M.; Roberti, G.; Carnevale, C.; Tanga, L.; et al. Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics. Pharmaceutics 2026, 18, 61. https://doi.org/10.3390/pharmaceutics18010061

AMA Style

Cavaterra D, Giammaria S, Pandino I, Zingale GA, Delli Paoli V, Fiore R, Michelessi M, Roberti G, Carnevale C, Tanga L, et al. Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics. Pharmaceutics. 2026; 18(1):61. https://doi.org/10.3390/pharmaceutics18010061

Chicago/Turabian Style

Cavaterra, Dario, Sara Giammaria, Irene Pandino, Gabriele Antonio Zingale, Valerio Delli Paoli, Rebecca Fiore, Manuele Michelessi, Gloria Roberti, Carmela Carnevale, Lucia Tanga, and et al. 2026. "Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics" Pharmaceutics 18, no. 1: 61. https://doi.org/10.3390/pharmaceutics18010061

APA Style

Cavaterra, D., Giammaria, S., Pandino, I., Zingale, G. A., Delli Paoli, V., Fiore, R., Michelessi, M., Roberti, G., Carnevale, C., Tanga, L., Cazzato, D., Peroni, E., Grasso, G., Manni, G., Bocedi, A., Oddone, F., Coletta, M., Sbardella, D., & Tundo, G. R. (2026). Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics. Pharmaceutics, 18(1), 61. https://doi.org/10.3390/pharmaceutics18010061

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