Redox regulation of telomerase and telomeres in cancer: a critical appraisal of exposure, causality and molecular directness.

Authors

Mohsen Tatar, Mehdi Khorrami, Fatemeh Kazemi, Mehdi Masoumi, Shakour Babaei, Mahsan Khorrami

Published in

Molecular biology reports. Volume 53. Issue 1. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Telomerase reactivation and altered redox metabolism co-occur in most cancers, but the literature joining them is hard to read whole. We separate it into five propositions - redox control of telomerase, telomerase reverse transcriptase (TERT)-dependent control of redox metabolism, oxidative telomere damage, redox-associated alternative lengthening of telomeres, and therapeutic translation - and appraise each along four easily conflated axes: exposure, model, causal test and molecular directness. Much disagreement then reflects design heterogeneity rather than genuine conflict, and one common design is weaker than it appears: millimolar thiol given before a thiol-reactive electrophile cannot separate restored antioxidant capacity from chemical quenching of the compound. Causal strength and molecular directness vary independently. The best-supported redox findings - peroxide-driven Src/Ran-dependent TERT nuclear export, and glutathione depletion with repletion - rest on necessity and rescue but remain pathway-mediated, in transfected or non-cancer systems. The most direct chemistry is biochemical and telomeric: lesion identity and position govern shelterin binding, G-quadruplex folding, repair and telomerase extension, and one acute 8-oxoguanine event causes dysfunction without shortening. We identified no study causally linking a residue-resolved oxidative modification of endogenous TERT to altered assembly, localization or catalysis; imetelstat is the translational counterpart, its randomized efficacy established but redox engagement and telomere pharmacodynamics unmeasured. We set out the measurements that would close both gaps.

PMID:
42801356
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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