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

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.