The central character of this molecular triangle is glycogen synthase kinase-3β, a serine/threonine kinase first identified for its role in glycogen metabolism but now recognized as a signaling hub touching nearly every corner of the cell. GSK-3β is unusual among kinases in that it prefers substrates already phosphorylated by other enzymes, such as casein kinase 1, ERK, p38MAPK, and AMPK, allowing it to act as a second-messenger amplifier within pre-activated pathways. Its activity is controlled by a delicate phosphorylation balance: inhibitory phosphorylation at Ser9—carried out by Akt, PKA, p90RSK, and p70S6K—silences the kinase, while phosphorylation at Tyr216, mediated by Fyn and PYK2 or by autophosphorylation, restores full catalytic power. Protein phosphatases PP1 and PP2A can reverse the Ser9 mark, meaning the cell constantly recalibrates GSK-3β output in response to upstream signals.

What makes GSK-3β so vexing for oncologists is its radical context dependency. In tumors driven by aberrant Wnt/β-catenin signaling, active GSK-3β promotes β-catenin degradation and suppresses proliferation—acting as a tumor suppressor. Yet in cancers characterized by chronic NF-κB activation or inflammatory signaling, the very same kinase enhances NF-κB–dependent transcription and supports tumor survival and chemoresistance. The review catalogs this duality across tumor types with unusual precision. In hepatocellular carcinoma, GSK-3β is overexpressed and promotes proliferation, colony formation, and resistance to sorafenib, yet pharmacological inhibition with tideglusib restores RARβ signaling and sensitizes tumors to therapy. In pancreatic ductal adenocarcinoma, GSK-3β enhances NF-κB activity and drives proliferation, but its inhibition paradoxically increases EMT-associated transcription factors such as Snail and Zeb1, potentially promoting invasion. In breast cancer, kinase-dead GSK-3β mutants increased resistance to doxorubicin and tamoxifen and promoted clonogenic growth, while constitutively active GSK-3β was less permissive—one of the clearest demonstrations that GSK-3β is a context-dependent regulator of drug response rather than a simple oncogene.

This signaling plasticity is not random; it is orchestrated by upstream pathway dominance. Loss of PTEN or hyperactivation of Akt leads to inhibitory Ser9 phosphorylation of GSK-3β, altering its downstream targets. Cytoplasmic versus nuclear localization determines whether GSK-3β preferentially regulates oncogenic transcription factors like NF-κB and Snail or cell-cycle regulators like cyclin D1 and c-Myc. The kinase’s role may even evolve during tumor progression, functioning as a tumor suppressor in early stages while promoting invasion, therapy resistance, or metastatic traits later on. The therapeutic implication is profound: successful clinical translation requires stratification based on pathway dominance rather than indiscriminate kinase inhibition.

Alongside GSK-3β, the review examines two tumor suppressors whose loss is consistently linked to aggressive disease. The Raf kinase inhibitor protein (RKIP) is underexpressed in many cancers and acts as a metastasis suppressor by binding to Raf-1 and blocking phosphorylation of MEK, thereby constraining the MAPK/ERK cascade. RKIP also inhibits NF-κB activation by blocking IκB phosphorylation by IKK family kinases, and it regulates tumor cell resistance to both chemotherapy and immunotherapy. In human breast cancer, RKIP must be downregulated for metastasis to develop; patients with reduced RKIP exhibit larger tumors and higher grade, and RKIP mRNA levels are significantly lower in metastatic compared to non-metastatic disease. In gastric cancer, RKIP is lost in approximately 56 percent of primary tumors and absent in roughly 90 percent of lymph node metastases. A meta-analysis of 19 studies encompassing around 3,700 patients confirmed that RKIP loss independently predicts poor overall survival in digestive-tract cancers, with a hazard ratio of 0.55.

PTEN, the phosphatase and tensin homolog, is the central negative regulator of the PI3K/Akt pathway, dephosphorylating PIP3 back to PIP2 and thereby halting mitogenic signaling. PTEN is either mutated, underexpressed, or deleted in a large percentage of human cancers, with prevalence ranging from 50 to 80 percent in endometrial cancer—the highest rate of any solid tumor—to 30 to 40 percent in glioblastoma and 17 to 61 percent in prostate cancer. PTEN loss sustains Akt activation, which in turn phosphorylates GSK-3β at Ser9, altering its substrate specificity and signaling role. The review emphasizes that PTEN and RKIP are frequently co-dysregulated and linked through a dysregulated NF-κB/Snail/YY1 loop: hyperactivation of NF-κB promotes overexpression of YY1 and Snail, which suppress both RKIP and PTEN, reinforcing a feed-forward mechanism that enhances survival signaling, EMT, and resistance to therapy.

The review also highlights how post-translational modifications dynamically regulate this axis. GSK-3β activity is controlled by site-specific phosphorylation at Ser9 and Tyr216, but these marks do not simply switch the kinase on or off—they can alter substrate preference, subcellular localization, and signaling integration. PTEN is subject to extensive C-terminal phosphorylation by CK2 and GSK-3β, which can stabilize the protein while simultaneously reducing its lipid phosphatase activity by promoting a closed conformation—uncoupling PTEN abundance from functional output. RKIP undergoes a phosphorylation-dependent functional switch at Ser153 by PKC, which releases Raf-1 and redirects RKIP to inhibit GRK2, illustrating how the molecule can dynamically alternate between suppressing oncogenic signaling and modulating alternative pathways depending on cellular context.

On the therapeutic front, the review catalogs the most advanced clinical development in this area. LY2090314, an ATP-competitive inhibitor with sub-nanomolar potency against GSK-3β (IC50 approximately 0.9 nM), entered early-phase clinical evaluation in advanced solid tumors and hematologic malignancies but was limited by toxicity and a narrow therapeutic window. Elraglusib (9-ING-41), a maleimide-based ATP-competitive inhibitor with low-micromolar biochemical potency (IC50 approximately 0.7 µM), has progressed into phase I/II trials both as monotherapy and in combination with chemotherapy, with a phase II study in metastatic pancreatic ductal adenocarcinoma reporting objective responses and disease control when combined with gemcitabine and nab-paclitaxel. Tideglusib, an irreversible non-ATP-competitive inhibitor originally developed for neurodegenerative diseases, has shown preclinical promise in sensitizing glioblastoma xenografts to temozolomide and enhancing sorafenib activity in hepatocellular carcinoma models. Early-phase trials of elraglusib have demonstrated a favorable safety profile, with predominantly low-grade and manageable adverse events such as fatigue, gastrointestinal symptoms, and transient visual disturbances.

The review also connects this axis to immunotherapy resistance. GSK-3 inhibitors such as GSK3i and SB415286 downregulate transcription of programmed cell death protein 1 (PD-1) in CD8+ T cells, enhancing cytotoxic function and providing a rationale for combining GSK-3β inhibitors with PD-1/PD-L1 blockade. Conversely, PTEN loss is associated with immune-excluded tumor microenvironments, reduced T-cell infiltration, and resistance to immune checkpoint inhibitors, with low PTEN expression correlating with poor response to immunotherapy in non-small-cell lung cancer and breast cancer cohorts. RKIP downregulation, meanwhile, sustains NF-κB hyperactivation and maintains a tumor-intrinsic resistance state that limits the efficacy of checkpoint blockade. Nitric oxide donors and proteasome inhibitors such as NPI-0052 and bortezomib have been shown to sensitize resistant cancer cells by inhibiting NF-κB and its downstream target Snail, resulting in RKIP induction and reversal of EMT, migration, and invasion.

Perhaps the most sobering insight from the review concerns the challenges of clinical translation. In breast cancer cell models, inhibition of GSK-3β increased resistance to doxorubicin and tamoxifen, yet the same cells became more sensitive to MEK or mTOR blockade—demonstrating that the resistance phenotype is network-dependent rather than GSK-3β-alone dependent. In p53-null colon cancer, by contrast, GSK3B silencing restored chemotherapy sensitivity and drove necroptotic death. In colorectal cancer models harboring PIK3CA and TCF7 mutations, inhibition of GSK3β restored sensitivity to the dual PI3K/mTOR inhibitor gedatolisib by suppressing aberrant WNT/β-catenin signaling. The fundamental challenge in targeting PTEN and RKIP stems from the therapeutic necessity to restore lost function, where neither the lipid phosphatase activity of PTEN nor the protein-scaffolding function of RKIP presents a conventional activation pocket amenable to small-molecule agonism. Only eight FDA-approved compounds have been reported to increase RKIP promoter activity in breast cancer cells, and none is a clinically validated activator. The review concludes that the GSK-3β/RKIP/PTEN axis functions as a dynamic signaling hub whose dysregulation is rarely driven by a single molecule, but rather by disruption of integrated circuitry—and that a systems-level, context-guided approach, incorporating biomarker-driven patient selection, optimized dosing, and combination strategies, will be essential to translate this complex molecular dialogue into practical, patient-centered strategies for better cancer care.

Subject of Research: The cross-talk between GSK-3β, RKIP, and PTEN as potential targets for therapeutic implications in cancer: a comprehensive insight

Article Title: The cross-talk between GSK-3β, RKIP, and PTEN as potential targets for therapeutic implications in cancer: a comprehensive insight

Article References: Mosalam, E. M., Abdallah, M. S., Gardouh, A. R., Hamza, E., Bahaa, M. M., Nazih, M., Al-Dhelaan, R. A., & Kamal, N. (2026). The cross-talk between GSK-3β, RKIP, and PTEN as potential targets for therapeutic implications in cancer: a comprehensive insight. Journal of Pharmacy & Pharmaceutical Sciences, 29, Article 16610. https://doi.org/10.3389/jpps.2026.16610

Image Credits: AI Generated

DOI: 10.3389/jpps.2026.16610

Keywords: cross-talk, between, GSK-3, RKIP, PTEN, potential, targets, therapeutic, implications, cancer, comprehensive, insight

The bioenergetic argument rests on a well-documented observation that has long puzzled researchers: the brains of people with Alzheimer’s disease are energy-starved. Fluorodeoxyglucose positron emission tomography, a scanning technique that tracks glucose consumption, consistently shows reduced metabolic activity in brain regions affected early by the disease, and this hypometabolism can appear years before memory symptoms emerge. At the cellular level, mitochondria, the organelles that generate adenosine triphosphate, or ATP, show impaired function across the electron transport chain. Enzymes of the tricarboxylic acid cycle, including the pyruvate dehydrogenase complex and the alpha-ketoglutarate dehydrogenase complex, are inhibited in Alzheimer’s tissue, and amyloid-binding alcohol dehydrogenase, an enzyme whose activity is blocked by amyloid-beta, further undermines mitochondrial metabolism. The result is a vicious cycle in which failing mitochondria produce more reactive oxygen species, which damage proteins, lipids, and DNA, which in turn further cripple the cell’s power plants.

Where does lithium enter this picture? The review’s central claim is that lithium ion, at physiological concentrations, acts as a regulator of multiple bioenergetic pathways, and that a decline in endogenous lithium with aging or disease removes this regulation. Epidemiological studies have reported inverse associations between trace lithium levels in drinking water and dementia prevalence across regions, an observation that first drew attention to lithium’s potential relevance beyond psychiatry, where lithium salts have been a mainstay treatment for bipolar disorder for more than seventy years. The authors argue that the convergence of these population-level signals with mechanistic data on lithium’s intracellular targets justifies treating lithium deficiency as a modifiable risk factor rather than a biochemical curiosity.

The best-characterized molecular target of lithium is glycogen synthase kinase-3, and specifically its beta isoform, GSK-3beta. This enzyme sits at a remarkable intersection of Alzheimer’s pathology. It phosphorylates tau protein, promoting the aggregation that forms neurofibrillary tangles; it modulates amyloid precursor protein processing in ways that can favor production of amyloid-beta; and it regulates insulin signaling and glucose metabolism, linking directly to the bioenergetic deficits described above. Lithium inhibits GSK-3 through direct competition with magnesium binding and through indirect mechanisms involving the Wnt signaling pathway, which stabilizes beta-catenin and supports neuronal survival. By damping GSK-3 activity, lithium simultaneously addresses protein aggregation, metabolic dysfunction, and synaptic resilience, a breadth of action that conventional single-target drugs have struggled to replicate.

Beyond GSK-3, the review details lithium’s effects on mitochondria themselves. Lithium has been reported to improve mitochondrial membrane potential, support the electron transport chain, and modulate the mitochondrial permeability transition pore, whose pathological opening triggers cell death. It engages the PINK1-dependent mitophagy pathway, the quality-control system that identifies and recycles damaged mitochondria, and it activates AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, master switches that coordinate mitochondrial biogenesis and energy sensing. On the antioxidant front, lithium appears to engage the Nrf2 pathway, which drives expression of cytoprotective enzymes such as heme oxygenase-1 through the antioxidant response element, thereby blunting the oxidative damage that accompanies mitochondrial failure. These mechanisms collectively suggest that lithium does not merely protect neurons from stress but actively rebuilds the energy infrastructure of the cell.

Neuroinflammation provides a third pillar of the hypothesis. Activated microglia, the brain’s resident immune cells, release inflammatory cytokines including interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha, and they assemble the NLRP3 inflammasome, a molecular platform that amplifies inflammatory signaling. Chronic neuroinflammation is now recognized as a core feature of Alzheimer’s disease, and it both drives and is driven by metabolic failure, because inflamed glial cells consume energy and disrupt neuronal metabolism. The review summarizes evidence that lithium suppresses nuclear factor kappa B signaling and NLRP3 inflammasome activation, reducing the inflammatory cascade. At the same time, lithium increases brain-derived neurotrophic factor and its receptor TrkB, supporting synaptic plasticity and neuronal survival, and it modulates cyclin-dependent kinase 5 and ubiquitin-specific protease 11, additional enzymes implicated in tau pathology. The picture that emerges is of a single ion touching nearly every major node of the disease network.

The therapeutic challenge is that classic lithium carbonate, the formulation used in psychiatry, requires blood levels that carry a narrow therapeutic window and risks of thyroid, kidney, and gastrointestinal toxicity, particularly in older adults whose renal function, measured by estimated glomerular filtration rate, is already declining. The review therefore devotes substantial attention to next-generation lithium formulations designed to deliver lithium to the brain at microdose levels while minimizing systemic exposure. Among these, tri-lithium pyrroloquinoline quinone, or Li3PQQ, receives particular emphasis. Pyrroloquinoline quinone is a redox-active compound with its own mitochondrial and neuroprotective properties, and coupling it to lithium creates a dual-action molecule in which the carrier itself supports bioenergetics. Such formulations, the authors argue, could achieve cerebral bioenergetic restoration without the serum concentrations that make conventional lithium therapy impractical for dementia patients.

Clinical evidence to date remains preliminary but suggestive. Small trials and observational studies of microdose lithium in mild cognitive impairment, the stage preceding overt Alzheimer’s dementia, have reported slowing of cognitive decline on measures such as the Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and reductions in progression markers such as the Clinical Dementia Rating-Sum of Boxes. The review is careful to acknowledge that these studies are limited in size and duration, and that definitive conclusions require larger, randomized, biomarker-stratified trials. It also emphasizes that lithium’s effects must be monitored with therapeutic drug monitoring, thyroid-stimulating hormone measurement, and renal function testing, even at low doses, to ensure safety in the elderly population most at risk.

Perhaps the most forward-looking element of the review is its proposed precision framework for lithium-based therapy. The authors argue that intervention should begin early, ideally at the mild cognitive impairment stage or even earlier, because bioenergetic failure is among the earliest detectable changes and becomes progressively harder to reverse as neurons die. They advocate biomarker-guided patient selection, using fluorodeoxyglucose PET to identify individuals whose disease is dominated by metabolic dysfunction, and potentially measuring endogenous lithium levels in cerebrospinal fluid or blood to identify those most likely to benefit. They further propose rational combination therapies, pairing lithium with anti-amyloid antibodies, non-steroidal anti-inflammatory drugs, or other metabolic interventions, on the logic that a multi-mechanism disease demands multi-mechanism treatment. In this framework, lithium would not replace existing therapies but anchor a bioenergetic arm of a combination regimen.

The lithium deficiency hypothesis is not without open questions. The mechanisms by which the body regulates endogenous lithium, how its levels change with age, and whether deficiency is a cause or consequence of neurodegeneration remain incompletely understood, and population associations between environmental lithium and dementia risk do not by themselves establish causation. Yet the review’s synthesis arrives at a moment when the Alzheimer’s field is actively searching beyond amyloid for disease-modifying approaches, following the modest clinical benefits of recently approved anti-amyloid therapies. If the bioenergetic framing proves correct, the implications are striking: one of psychiatry’s oldest and cheapest medicines, reengineered for the brain and deployed early, could address the metabolic engine failure that precedes and perhaps drives the pathology everyone has been watching. The authors’ conclusion is measured but ambitious, proposing that by targeting cerebral bioenergetic failure, lithium-based strategies may open a new door for disease-modifying therapy against Alzheimer’s disease.

Subject of Research: The role of endogenous lithium deficiency in cerebral bioenergetic failure and therapeutic intervention in Alzheimer's disease

Article Title: Lithium deficiency in Alzheimer’s disease: from cerebral bioenergetic failure to therapeutic intervention

Article References: Li, S., Lei, Z., Cai, C., Tan, J., & Chen, J. (2026). Lithium deficiency in Alzheimer’s disease: from cerebral bioenergetic failure to therapeutic intervention. BMC Medicine. https://doi.org/10.1186/s12916-026-05245-5

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05245-5

Keywords: Alzheimer's disease, lithium, bioenergetics, mitochondria, GSK-3, neuroinflammation, disease-modifying therapy, mild cognitive impairment, Li3PQQ, metabolic dysfunction, neuroprotection, BMC Medicine