SYSTEMATIC REVIEW article
Front. Oncol.
Sec. Cancer Metabolism
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1647054
Hydrated Proton Complexes Supplementation for Tumor Microenvironment Reprogramming: A Bioenergetic Strategy Targeting the Warburg Effect and Mitochondrial Dysfunction
Provisionally accepted- 1Elastro Crete, LLC, Veyo, United States
- 2Federal University of Santa Maria, Santa Maria, Brazil
- 3Oncocenter Clinic, Santa Maria, Brazil
- 4Institute AuBento, Santa Maria, Brazil
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Background: The tumor microenvironment (TME) is characterized by a reversed pH gradient—acidic extracellular and alkaline intracellular conditions—arising from mitochondrial dysfunction, metabolic reprogramming, and dysregulated proton transport. These alterations establish a permissive niche for tumor progression, immune evasion, and resistance to therapy. Although the TME is increasingly recognized as a key determinant of cancer behavior, effective and targeted strategies for its bioenergetic reprogramming remain scarce. Objectives: This study introduces and evaluates Eigen/Zundel Complexes-Rich Water (EZC-Rich Water) as a novel hydrated proton supplementation strategy capable of targeting Warburg-induced proton dysregulation and restoring mitochondrial function, while stabilizing electrochemical membrane dynamics within the TME. Methods: A structured translational research design was implemented, combining Work Breakdown Structure (WBS), Open Innovation, and Design Thinking methodologies. This approach enabled the identification of Fundamental Points of View (FPV’s)—physiological targets underlying TME dysfunction—and Critical Success Factors (CSF’s)—mechanistic requirements for therapeutic efficacy. Multicriteria decision analysis was applied to integrate findings from oncology, bioenergetics, and physical chemistry, linking hydrated proton supplementation to improved zeta potential, electrosmotic flow, mitochondrial coupling, and redox regulation. Results: Integrative analyses demonstrated that EZC-Rich Water delivers metastable hydrated proton clusters (H₉O₄⁺ and H₅O₂⁺) that support selective and efficient proton transfer via the Grotthuss mechanism. This supplementation facilitates compartmentalized acid–base modulation without inducing systemic acidosis, aligning with prioritized FPV’s and validated CSF’s. The proposed strategy shows translational potential to correct pH inversion, optimize oxidative phosphorylation, and restore bioenergetic integrity in the TME. Conclusion: Hydrated proton supplementation through EZC-Rich Water represents an innovative bioenergetic intervention with potential to reprogram the tumor microenvironment. By targeting core metabolic dysfunctions such as the Warburg effect and mitochondrial uncoupling, this clinically adaptable and low-risk strategy introduces a new paradigm in nutritional oncology. Further preclinical and clinical studies are warranted to validate its efficacy, safety, and translational applicability in oncology and related metabolic disorders.
Keywords: Tumor Microenvironment, Hydrated proton complexes, Mitochondrial dysfunction, Warburg effect, redox signaling, Bioenergetic reprogramming
Received: 14 Jun 2025; Accepted: 04 Aug 2025.
Copyright: © 2025 Edgar, Lopes, Lopes, Felin, Felin and Gaspary. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Luis Felipe Dias Lopes, Federal University of Santa Maria, Santa Maria, Brazil
João Francisco Pollo Gaspary, Institute AuBento, Santa Maria, Brazil
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