The research team, led by Sai Long and Yao Li of the School of Physical Education at Jiangxi Normal University Science and Technology College in China, conducted the review in accordance with the PRISMA 2020 reporting standard and prospectively registered the protocol in PROSPERO. They searched six major databases—PubMed, Embase, Cochrane CENTRAL, Scopus, Web of Science, and SPORTDiscus—from inception through June 2026, screening 4,694 records and ultimately including 25 trials published between 2003 and 2026. The trials spanned Asia, Europe, North America, Australia, and the Middle East, and the exercise programs they tested were remarkably diverse: aerobic training, resistance training, high-intensity interval training, combined regimens, Pilates, yoga, and walking-based programs, lasting anywhere from six weeks to twelve months.

The headline numbers are striking. Across 15 trials involving 504 participants, exercise reduced alanine aminotransferase, or ALT, by a mean of 7.33 units per liter compared with control conditions, with a 95 percent confidence interval of −10.71 to −3.95. Aspartate aminotransferase, or AST, fell by 5.52 units per liter across 13 trials with 439 participants. Body mass index dropped by a pooled 1.54 kilograms per square meter across 17 trials, and peak or maximal oxygen uptake—VO2peak or VO2max, the gold standard measure of cardiorespiratory fitness—rose by 4.08 milliliters per kilogram per minute across seven trials. These are not trivial changes. ALT and AST are the workhorse blood markers of hepatocellular injury, and reductions of this magnitude are comparable to those seen with some pharmacological interventions studied in fatty liver disease.

But the analysis also delivered a sobering counterpoint: the pooled effects on liver fat itself, insulin resistance measured by HOMA-IR, and longer-term glycemic control measured by HbA1c did not reach statistical significance. Seven trials with 233 participants contributed liver fat or steatosis data, yielding a standardized mean difference of −0.36 with a confidence interval spanning −0.93 to 0.20—suggestive of a benefit but far from conclusive. HOMA-IR, pooled from six trials, showed a non-significant reduction of 0.49, and HbA1c, also from six trials, showed a non-significant drop of 0.18 percentage points. The authors are careful to note that improvements in BMI, glycemic markers, or fitness are clinically relevant in the broader cardiometabolic context of MASLD but should not be read as direct evidence that the liver disease itself has resolved.

The methodological machinery behind these conclusions is worth unpacking, because it reveals both the strength and the fragility of the evidence. The researchers used the Cochrane RoB 2 tool to assess risk of bias and found that no trial was judged at high overall risk; roughly half were rated low risk and the remainder had some concerns, most often involving incomplete reporting of randomization procedures or missing outcome data. They then applied the GRADE framework to rate certainty of evidence, and the results were uneven: moderate certainty for the ALT and BMI findings, low certainty for cardiorespiratory fitness, and very low certainty for AST, liver fat, HOMA-IR, and HbA1c. That gradation matters enormously for how clinicians and patients should weigh each result.

Heterogeneity was a persistent theme. Statistical heterogeneity, quantified by the I² statistic, reached 71.3 percent for ALT, 93.8 percent for AST, and 72.3 percent for VO2peak—meaning that the trials varied substantially in the size of the effects they reported. The authors addressed this in several ways. They ran leave-one-out sensitivity analyses, which generally preserved the direction of the pooled estimates. They conducted duration subgroup analyses, splitting trials into those lasting twelve weeks or less versus longer programs. Intriguingly, shorter interventions showed a larger ALT reduction—10.09 units per liter versus 2.46 units per liter for longer programs, a statistically significant difference. But the authors caution against interpreting this as evidence that shorter programs are physiologically superior; the comparison is observational, and duration may simply proxy for differences in baseline enzyme levels, exercise intensity, supervision, and adherence across trials.

One trial in particular shaped the AST picture. A 2025 study by Kim and colleagues reported an unusually large AST reduction, and when the authors excluded it in a dedicated sensitivity analysis, the pooled effect shrank from 5.52 to 3.25 units per liter while heterogeneity collapsed from 93.8 percent to 33.5 percent. The direction of the benefit held, but the magnitude proved sensitive to a single influential study. For BMI, funnel-plot asymmetry detected by Egger regression—significant at p=0.018—raised the possibility of small-study effects, though the authors stopped short of calling it definitive publication bias, noting that asymmetry can arise from multiple sources and that the BMI dataset included small, imprecise trials. No such asymmetry was detected for ALT or AST.

Perhaps the most conceptually important contribution of the review is its insistence on separating domains of response. ALT and AST are markers of hepatocellular injury, not direct measures of hepatic function, so their reduction signals biochemical improvement rather than histological resolution. Liver fat was measured with non-equivalent methods across trials—some used MRI-derived proton density fat fraction or proton magnetic resonance spectroscopy, which directly quantify intrahepatic lipid, while others used the controlled attenuation parameter from transient elastography, an indirect marker. Pooling these on a standardized scale cannot erase that measurement mismatch. Meanwhile, gains in aerobic capacity are biologically consistent with improved skeletal-muscle oxidative capacity, glucose disposal, fatty-acid utilization, and whole-body metabolic flexibility—adaptations that may reduce metabolic substrate delivery to the liver, but which the non-significant HOMA-IR and HbA1c results show were not uniform across metabolic domains.

The findings arrive amid a rapidly evolving evidence landscape. A 2024 network meta-analysis by Huang and colleagues ranked exercise modalities across metabolic and liver-function outcomes; a 2025 synthesis examined Mediterranean diet combined with exercise; and a 2026 meta-analysis by Wang and colleagues focused specifically on high-intensity interval training versus moderate-intensity continuous training, including dose-response analyses. The new review distinguishes itself by treating structured exercise as a single common exposure and applying one consistent post-intervention analytical framework across seven prespecified outcome domains. It also reports prediction intervals—ranges describing the expected effect in a future, comparable setting—which for ALT, BMI, and VO2peak all crossed the null, a statistical way of saying that the average benefit does not guarantee a uniform response in every clinical context.

For the millions of people living with MASLD, the practical message is cautiously encouraging. Structured exercise emerges as a physiologically relevant component of management, particularly when the goals include lowering elevated liver enzymes, reducing body mass, and building cardiorespiratory fitness. But the authors are explicit that the optimal prescription—the right combination of mode, intensity, and duration to produce reproducible hepatic adaptations independent of weight loss—remains unknown. They call for future trials that report exercise dose and adherence in sufficient detail, use standardized and sensitive measures of intrahepatic fat, and prespecify metabolic and cardiorespiratory outcomes. Until then, the liver enzyme improvements documented here stand as the most consistent signal that exercise does something real for the fatty liver, even as the deeper question of whether it reshapes the diseased organ itself awaits stronger evidence.

Subject of Research: Effects of exercise training on hepatic, metabolic, and cardiorespiratory outcomes in adults with metabolic dysfunction-associated steatotic liver disease

Article Title: Exercise training improves hepatic enzymes, body mass index, and cardiorespiratory fitness in adults with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis

Article References: Exercise training improves hepatic enzymes, body mass index, and cardiorespiratory fitness in adults with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis. (n.d.). https://doi.org/10.3389/fphys.2026.1976073

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1976073

Keywords: MASLD, NAFLD, exercise training, liver enzymes, ALT, AST, body mass index, cardiorespiratory fitness, meta-analysis, liver fat, insulin resistance, HOMA-IR

The research, published in BMC Pediatrics by a team led by Oswald Kakule Maghuli of Kampala International University’s Western Campus, followed 421 term neonates who were born with perinatal asphyxia, defined in the study by an Apgar score of less than 7 at five minutes of age. The Apgar score is a rapid bedside assessment of a newborn’s condition, evaluating heart rate, breathing, muscle tone, reflexes, and color, and a low score at five minutes signals that the infant has not transitioned well to life outside the womb. These infants were enrolled across three tertiary referral hospitals in Uganda, institutions that handle the sickest newborns in their regions and where birth asphyxia remains a daily reality on pediatric wards.

The study’s design was deliberately rigorous. It was a hospital-based prospective cohort study, meaning that infants were enrolled at admission and followed forward in time rather than looking backward at existing records. Each participant provided two milliliters of venous blood at three fixed time points: within the first day of life, on the third day, and on the seventh day. The samples were analyzed for four liver-related enzymes: aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). These enzymes normally reside inside liver cells, and when hepatocytes are damaged, they leak into the bloodstream, making elevated levels a sensitive biochemical fingerprint of liver injury. The researchers set a conservative diagnostic threshold: a newborn was classified as having hypoxic hepatitis only if at least three of the four enzymes were deranged, reducing the chance that isolated, clinically insignificant fluctuations would inflate the results.

The findings were striking. Hepatic injury was detected in 214 of the 421 participants, or 50.8 percent, on the first day of life. By day three, the number had fallen to 137 infants, or 32.5 percent, and by day seven it had dropped further to 69 infants, or 16.4 percent. Overall, 222 newborns, slightly more than half of the cohort, showed hepatic injury at at least one point during the seven-day observation window, yielding an incidence of hypoxic hepatitis of 52.7 percent, with a 95 percent confidence interval of 48.2 to 57.5 percent. That confidence interval, which does not fall below 48 percent, indicates that even at the most conservative estimate, nearly one in two asphyxiated newborns in these hospitals experienced measurable liver injury.

Perhaps the most clinically consequential finding was the timing of the injury. Of the newborns who developed hypoxic hepatitis, 96.4 percent were first diagnosed on the first day of life. Only eight infants, or 3.6 percent, had the diagnosis first made on the third day, and not a single participant had hypoxic hepatitis first detected on the seventh day. In other words, the liver damage inflicted by oxygen deprivation is essentially an immediate event, unfolding in the hours immediately surrounding birth rather than emerging gradually over the first week. This temporal pattern mirrors the underlying biology: the liver is one of the most metabolically active organs in the newborn body, with high energy demands to support glucose production, protein synthesis, bilirubin processing, and the detoxification functions that a newborn suddenly must perform independently after the placenta is severed.

When oxygen delivery falters, the body responds by redistributing blood flow away from less critical organs toward the brain and heart, a survival mechanism known as the dive reflex. The liver, along with the kidneys and gastrointestinal tract, is among the first organs to be sacrificed in this redistribution. The resulting ischemia, combined with the reperfusion injury that occurs when oxygenated blood returns to the deprived tissue, generates a cascade of reactive oxygen species and inflammatory mediators that damage hepatocyte membranes. Because the neonatal liver is already operating near its metabolic capacity, this insult can quickly translate into measurable enzyme leakage, and in severe cases into coagulopathy, hypoglycemia, and impaired drug metabolism, all of which complicate the care of an already fragile infant.

The study cohort was composed slightly more of males than females, with 53.4 percent boys and 46.6 percent girls, a distribution consistent with the well-documented male vulnerability to perinatal complications. The researchers note that the burden of birth asphyxia and its complications falls disproportionately on resource-limited settings such as Uganda, where access to advanced neonatal intensive care, therapeutic hypothermia, and sophisticated monitoring is limited. In such environments, a complication like hypoxic hepatic injury can be easily overlooked, because clinical attention is understandably dominated by the neurological manifestations of hypoxic-ischemic encephalopathy, including seizures, poor feeding, and altered consciousness. Yet unrecognized liver dysfunction can undermine the very treatments being delivered, altering the pharmacokinetics of anticonvulsant drugs and worsening bleeding risk during procedures.

Based on their findings, the authors recommend that all neonates with birth asphyxia be routinely screened for hepatic injury, and critically, that this screening be performed within the first 72 hours of life. The recommendation is grounded directly in the study’s temporal data: since virtually all cases were detectable by day one and none first appeared by day seven, a single early liver function test panel would capture the overwhelming majority of affected infants. In practical terms, this means that the same blood draw already being used for other neonatal assessments could be extended to include AST, ALT, ALP, and LDH, adding relatively little cost while potentially changing management for more than half of asphyxiated newborns in similar settings.

The implications extend beyond Uganda. Birth asphyxia accounts for a substantial share of the roughly 2.3 million neonatal deaths that occur globally each year, the majority concentrated in sub-Saharan Africa and South Asia. If the incidence observed in this Ugandan cohort is representative, hypoxic hepatic injury may be one of the most common, and most underdiagnosed, complications of perinatal oxygen deprivation worldwide. The study also highlights the value of prospective, multi-site designs in resource-limited settings, where much of the existing literature on neonatal organ injury derives from high-income countries with very different patient populations and care standards. By documenting the natural history of liver enzyme derangement across the first week of life, the researchers have created a baseline against which future interventions, whether hepatoprotective therapies, modified resuscitation protocols, or structured screening programs, can be evaluated.

For clinicians on the front lines, the message is direct: the liver is not a silent bystander in birth asphyxia. It is injured early, in most babies who are injured at all, and it can be detected with a simple, widely available panel of blood tests. For researchers, the study opens questions that the current data cannot answer, including how hepatic injury severity correlates with the degree of encephalopathy, whether early biochemical injury predicts longer-term outcomes such as growth and neurodevelopment, and whether targeted supportive care in the first days of life can attenuate the hepatic damage. What is already clear is that in the crowded pediatric wards of Uganda’s tertiary hospitals, and likely far beyond them, more than half of oxygen-deprived newborns carry a hidden hepatic burden that modern neonatal care can no longer afford to ignore.

Subject of Research: Hypoxic hepatic injury in term neonates with birth asphyxia in Uganda

Article Title: Incidence of hepatic injury in term asphyxiated neonates admitted in three tertiary hospitals in Uganda: a prospective study

Article References: Maghuli, O. K., Kitsamuli, J. N., Paluku Isombi, J., Shamavu, G. K., Mbekeeka, P., Nankunda, J., & Eldeen Mohamed, A. N. (2026). Incidence of hepatic injury in term asphyxiated neonates admitted in three tertiary hospitals in Uganda: a prospective study. BMC Pediatrics. https://doi.org/10.1186/s12887-026-06915-2

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DOI: 10.1186/s12887-026-06915-2

Keywords: birth asphyxia, hypoxic hepatitis, hepatic injury, neonates, liver enzymes, Uganda, Apgar score, AST, ALT, neonatal care, resource-limited settings, prospective cohort study

MASLD is the liver’s manifestation of metabolic syndrome, a spectrum that begins with simple fat accumulation and can progress to inflammation, known as steatohepatitis, and ultimately to fibrosis and cirrhosis. Lifestyle change remains the foundation of care, and while the thyroid hormone receptor agonist resmetirom and the GLP-1 receptor agonist semaglutide both won U.S. approval in 2024 and 2025 after demonstrating histological benefit, clinicians still lack a broad arsenal. Because dyslipidemia coexists with MASLD in an estimated 26 to 58 percent of cases, drugs that correct blood fats while calming the liver have long attracted interest. Fenofibrate, which activates the nuclear receptor PPARα and drives fatty acid oxidation, has shown hints of benefit in small studies, but its evidence base in fatty liver disease has never been strong enough to establish consensus.

Pemafibrate was engineered to solve a specific pharmacological problem. Rather than broadly activating PPARα the way older fibrates do, it binds selectively and induces ligand-specific conformational changes in the receptor that enhance transcriptional regulation of target genes. Approved in Japan in 2017, the drug had already shown promise in a phase 2 trial where it reduced alanine aminotransferase, or ALT, a sensitive marker of hepatocellular injury, and lowered liver stiffness on magnetic resonance elastography without raising serum creatinine. What remained unknown was whether this molecular refinement translated into clinical superiority over fenofibrate, and whether the drug’s effect scaled with dose. The PRESENT trial was designed to answer both questions simultaneously.

The investigators enrolled 360 participants, all Japanese, with imaging- or biopsy-confirmed fatty liver, triglycerides between 150 and 500 mg/dL, and elevated ALT despite at least three months of diet and exercise efforts. After randomization in equal proportions, 356 patients began treatment: 114 received high-dose pemafibrate at 0.4 mg daily, 117 received low-dose pemafibrate at 0.2 mg daily, and 125 received fenofibrate starting at 53.3 mg daily with cautious escalation permitted. The trial ran for 48 weeks of treatment with a six-week follow-up, and the primary endpoint was the change in ALT at 24 weeks, chosen for its clinical accessibility across the university hospitals and community clinics that participated. Randomization was stratified by diabetes status, triglyceride level, and FIB-4 index to keep the groups balanced, and a prespecified hierarchical testing procedure guarded against false-positive findings.

The results were striking. High-dose pemafibrate cut ALT by an average of 24.0 U/L, a 35.9 percent reduction, while low-dose pemafibrate achieved a 14.8 U/L drop, or 21.8 percent. Fenofibrate managed only a 4.22 U/L decline, essentially 2.1 percent. Both pemafibrate doses beat fenofibrate with high statistical significance under the trial’s fixed-sequence analysis, and, critically, the high dose outperformed the low dose, establishing a genuine dose-response relationship that no previous randomized trial in MASLD had demonstrated. Gamma-glutamyltransferase, another marker of hepatic stress, fell 46.3 percent with high-dose pemafibrate compared with 13.8 percent on fenofibrate, and lipid profiles improved across all three groups without significant differences between them.

The kidney findings may prove just as consequential as the liver data. Fenofibrate is notorious for raising serum creatinine, an effect that can trigger hospitalizations and nephrology referrals in older adults. In this trial, creatinine rose 10.9 percent and estimated glomerular filtration rate fell 9.8 percent in the fenofibrate arm at 24 weeks, whereas pemafibrate produced creatinine increases of just 4.3 percent and 2.1 percent at high and low doses respectively, with correspondingly smaller eGFR declines. The differences were statistically significant at both 24 and 48 weeks. The pharmacological explanation is elegant: fenofibrate is excreted primarily through the urine, while pemafibrate leaves the body mainly via bile. For the many MASLD patients who also carry diabetes, hypertension, or chronic kidney disease, this renal profile could reshape prescribing decisions.

Beyond the blood tests, imaging told a nuanced story. Magnetic resonance elastography, performed under a standardized protocol with central reading, showed liver stiffness falling 9.24 percent in the high-dose pemafibrate group and 8.40 percent in the low-dose group, while stiffness actually rose 3.56 percent on fenofibrate. Vibration-controlled transient elastography, assessed locally without centralized quality control, detected no significant changes in any group, a discrepancy the authors attribute to inter-site variability and MRE’s superior sensitivity for early fibrosis stages. The fibrosis biomarker M2BPGi, which reflects both scarring and inflammatory activity, dropped more than 21 percent with high-dose pemafibrate versus 3.2 percent with fenofibrate, while FIB-4, type IV collagen 7S, and ELF scores remained flat across the board. Liver fat content on MRI-PDFF did not change significantly, consistent with animal work suggesting pemafibrate shrinks individual lipid droplets and accelerates lipid turnover rather than reducing total hepatic triglyceride.

Safety data reinforced the drug’s favorable profile. Treatment-related adverse events numbered 8 in the high-dose pemafibrate arm, 6 in the low-dose arm, and 18 with fenofibrate, with no treatment-related serious events anywhere in the trial. Myalgia was the most common treatment-related complaint, and a single case of rhabdomyolysis in the high-dose pemafibrate group resolved spontaneously after discontinuation. Five hepatobiliary disorder events occurred exclusively in the fenofibrate group, and concomitant statin use, which affects roughly 40 percent of these patients, did not increase adverse events among pemafibrate recipients. Because fibrate-statin combinations carry well-known risks of muscle toxicity through pharmacokinetic interactions, pemafibrate’s minimal impact on statin metabolism adds another practical advantage for a population at elevated cardiovascular risk.

Perhaps the most intriguing finding emerged from the responder analysis. Patients who achieved at least a 30 percent ALT reduction were more likely to have started with higher baseline ALT above the trial median of 56 U/L, and, remarkably, to have lean MASLD defined as a body mass index below 23. Lean patients had nearly four times the odds of responding, an association that persisted in multivariate modeling. The authors suggest that lean MASLD represents a phenotype where hepatic lipid metabolism, rather than systemic metabolic inflammation, dominates the disease process, making a drug that selectively amplifies fatty acid oxidation especially effective. They also point to pemafibrate’s demonstrated suppression of the NLRP3 inflammasome and the NF-κB pathway, which curbs production of tumor necrosis factor-α and interleukin-1β, as a plausible mechanism for the anti-inflammatory signal captured by both ALT and M2BPGi.

The trial’s limitations temper the enthusiasm. There was no liver biopsy, the gold standard for grading steatohepatitis and fibrosis, the design was open-label, lifestyle factors were not standardized, and elastography was available only at some centers. The exclusively Japanese cohort also raises questions about generalizability to other populations. Still, the study’s scale, its stratified randomization, its sensitivity analyses, and its multimodal assessment of inflammation and fibrosis make it the most rigorous test of a selective PPARα modulator in MASLD to date. The authors call for long-term trials with histological endpoints to determine whether pemafibrate can truly modify disease course rather than merely improve surrogates. If those trials succeed, a drug once designed simply to lower triglycerides more cleanly may find its greatest legacy in the liver.

Subject of Research: Efficacy and renal safety of pemafibrate versus fenofibrate in metabolic dysfunction-associated steatotic liver disease with hypertriglyceridemia

Article Title: Dose-dependent efficacy and renal safety of pemafibrate versus fenofibrate in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia: a multicenter randomized controlled, open label trail

Article References: Iwaki, M., Tobita, H., Seko, Y., Kawata, K., Imajo, K., Nagai, K., Kessoku, T., Sakai, E., Nakada, Y., Koyama, S., Kurihashi, T., Yoshioka, W., Yunotani, S., Kohira, T., Takahashi, K., Yamamoto, M., Ishimaru, Y., Oza, N., Yamaguchi, Y., … Takahashi, H. (2026). Dose-dependent efficacy and renal safety of pemafibrate versus fenofibrate in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia: a multicenter randomized controlled, open label trail. eClinicalMedicine, Article 104226. https://doi.org/10.1016/j.eclinm.2026.104226

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DOI: 10.1016/j.eclinm.2026.104226

Keywords: pemafibrate, fenofibrate, MASLD, hypertriglyceridemia, PPAR alpha, liver fibrosis, ALT, renal safety, randomized controlled trial, M2BPGi, magnetic resonance elastography, selective PPAR alpha modulator

The review organizes the sprawling literature into five distinct propositions: redox control of telomerase activity, the reverse control of redox metabolism by the telomerase reverse transcriptase TERT, oxidative damage to telomeric DNA itself, redox-associated alternative lengthening of telomeres (ALT), and the therapeutic translation of all of the above. Each proposition is then graded separately for causal strength and molecular directness — two qualities the authors emphasize can vary completely independently. A finding can be causally robust yet mechanistically indirect, resting on a chain of downstream events; or it can be chemically precise yet demonstrated only in a test tube. Recognizing this independence, they contend, is the first step toward cleaning up a literature that has often graded studies on a single, misleading scale.

One of the sharpest methodological criticisms in the review targets a design that appears throughout the redox–telomerase literature: pretreating cells with millimolar concentrations of a thiol antioxidant such as N-acetylcysteine or glutathione before exposing them to a thiol-reactive electrophile. The problem, the authors explain, is one of chemical ambiguity. At those concentrations, the added thiol can simply quench the electrophile directly in the culture medium, a brute-force chemical reaction that has nothing to do with restoring the cell’s own antioxidant capacity. A rescue observed under those conditions cannot distinguish between genuine redox regulation of telomerase and trivial chemical neutralization of the insult. Because so many headline claims about antioxidants modulating telomerase rest on exactly this design, the finding casts a long shadow over a substantial fraction of the field.

What survives the audit? The authors identify the peroxide-driven, Src kinase–dependent phosphorylation of TERT at tyrosine 707, which triggers export of the enzyme from the nucleus via the Ran transport pathway, as among the best-supported redox findings. Hydrogen peroxide activates Src family kinases, phosphorylation at that specific residue promotes nuclear export, and the pathway satisfies necessity tests — blocking the kinase or the export machinery prevents the effect. Similarly well-supported is the glutathione depletion-and-repletion paradigm, in which lowering cellular glutathione alters telomerase activity and restoring it rescues the phenotype. Yet even these strongest findings, the review notes, remain pathway-mediated rather than chemically direct, and several were established in transfected systems or non-cancer cells such as endothelial cells and fibroblasts, leaving open questions about how faithfully they recapitulate events in an intact tumor.

Perhaps the most striking conclusion of the entire appraisal is a negative one. Despite decades of work, the authors identified no study that causally links a residue-resolved oxidative modification of endogenous TERT — a specific cysteine or tyrosine chemically modified by a defined reactive species inside a living cancer cell — to an altered outcome in telomerase assembly, subcellular localization, or catalytic activity. The distinction matters because redox biology has matured into a chemistry-first discipline: modern chemoproteomic tools can now identify which cysteines in a proteome are reactive, which ones get oxidized under defined conditions, and what functional consequences follow. TERT, with its multiple regulatory phosphorylation sites and its dependence on assembly with the telomerase RNA component, dyskerin and other partners, is precisely the kind of protein where such residue-level resolution should be achievable — and has not yet been delivered.

In contrast, the most molecularly direct chemistry in the entire field sits not on the protein but on the telomeric DNA itself. Guanine-rich telomeric repeats are exquisitely vulnerable to oxidation, and the review assembles a compelling body of biochemical work showing that the identity and position of an oxidative lesion govern nearly everything that matters: binding by the shelterin proteins TRF1 and TRF2, folding of the telomeric G-quadruplex structures that regulate telomerase access, recruitment of repair glycosylases such as OGG1 and the NEIL family, and the ability of telomerase to extend the chromosome end. An 8-oxoguanine lesion at one position of a G-quadruplex can destabilize the structure and promote telomerase extension, while the same lesion elsewhere blocks it — a position-dependent logic revealed through single-molecule and biochemical assays.

Even more provocative are recent findings showing that telomeric oxidation can drive dysfunction without any detectable shortening of the telomere. In work highlighted by the review, a single acute burst of targeted 8-oxoguanine damage at telomeres was sufficient to trigger rapid premature senescence, with telomere length remaining essentially unchanged. This decouples telomere dysfunction from the classical model in which telomeres erode gradually with each cell division, suggesting that a discrete oxidative event can flip the shelterin-bound chromosome end into a damage-signaling state essentially overnight. For cancer biology, the implication is double-edged: oxidative stress can push premalignant cells toward senescence, but it can also, under other conditions, push telomeres toward the recombination-based ALT pathway that a subset of tumors uses to elongate their chromosome ends.

On the therapeutic front, the review delivers a sobering translational parallel to its mechanistic gap. Imetelstat, the lipid-conjugated oligonucleotide that directly targets the telomerase RNA template, has now established randomized phase 3 efficacy in lower-risk myelodysplastic syndromes and has earned regulatory approval in the United States and a positive assessment in Europe. Yet the review points out that its redox engagement — whether the drug’s effects intersect with the oxidative stress programs that co-occur in treated tumors — has never been measured, nor have telomere pharmacodynamics been tracked in a way that connects clinical response to telomere biology at the molecular level. The most clinically successful telomerase-targeting agent, in other words, is as much of a black box with respect to redox as endogenous TERT is with respect to residue-level oxidation.

The review also surveys a crowded pipeline of redox-active agents with claimed telomerase effects: disulfiram and its copper diethyldithiocarbamate complex, which has been reported to induce both mitochondrial and telomerase dysfunction in lung cancer models; glutathione synthesis inhibitors such as butionine sulfoximine tested in combination regimens; the nucleoside analog 6-thio-deoxyguanosine, now in a phase 3 trial in non-small cell lung cancer, which recent structural work suggests stalls telomerase in a non-productive complex; and G-quadruplex ligands whose mechanisms have required substantial reevaluation. The authors’ framework provides a way to grade each of these claims, and the grades are frequently humbling: many rest on pharmacological exposures at concentrations far from physiological, in cell lines of uncertain provenance, with telomerase activity measured by the TRAP assay, which is itself known to be vulnerable to artifacts from redox-active compounds in the lysates.

What would close the gaps? The authors set out a concrete measurement agenda. For the protein side, it means deploying residue-resolved chemoproteomics and structural methods such as cryo-electron microscopy to catch endogenous TERT in the act of being oxidatively modified, and then testing causality with precisely engineered non-oxidizable mutants. For the telomere side, it means mapping lesion identity and position in cells, not just in synthetic oligonucleotides, and tracking how those lesions propagate through shelterin binding, repair, and telomerase extension. For the clinic, it means measuring telomere pharmacodynamics and redox biomarkers in imetelstat-treated patients. Until those measurements exist, the review concludes, the field should resist the temptation to narrate a tidy story of oxidants and telomeres — because the honest story, carefully audited, is one of strong chemistry at the chromosome end, plausible but unproven signaling at the enzyme, and a translational success whose deepest mechanisms remain to be written.

Subject of Research: Redox regulation of telomerase and telomeres in cancer

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

Article References: Tatar, M., Khorrami, M., Kazemi, F., Masoumi, M., Babaei, S., & Khorrami, M. (2026). Redox regulation of telomerase and telomeres in cancer: a critical appraisal of exposure, causality and molecular directness. Molecular Biology Reports, 53(1), Article 1638. https://doi.org/10.1007/s11033-026-12826-3

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DOI: 10.1007/s11033-026-12826-3

Keywords: telomerase, TERT, telomeres, redox biology, oxidative stress, cancer, 8-oxoguanine, glutathione, ALT, imetelstat, DNA damage, G-quadruplex