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CREB-PGC1α-UCP2 Axis Plays a Critical Role in AML Progression, Offering Potential Therapeutic Targets

Submitted:

23 June 2026

Posted:

24 June 2026

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Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the uncontrolled proliferation of immature myeloid cells and poor clinical outcomes, particularly in patients with relapsed or refractory disease. Increasing evidence suggests that metabolic reprogramming and mitochondrial adaptation play crucial roles in supporting leukemic cell survival, proliferation, and resistance to therapy. Among the emerging regulatory pathways involved in this process, the CREB–PGC1α–UCP2 signaling axis has been identified as a key mediator linking transcriptional regulation to mitochondrial metabolism in AML. CREB (cAMP Response Element-Binding Protein) is a transcription factor frequently overexpressed or constitutively activated in AML, where it promotes leukemic cell growth and survival through the regulation of genes involved in metabolism and mitochondrial function. One important downstream target of CREB is PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha), a master regulator of mitochondrial biogenesis and oxidative phosphorylation. Activation of PGC-1α enhances mitochondrial activity and metabolic flexibility, enabling AML cells to meet the increased bioenergetic and biosynthetic demands required for rapid proliferation. Furthermore, PGC-1α regulates the expression of UCP2 (Uncoupling Protein 2), a mitochondrial inner membrane protein that modulates reactive oxygen species production and maintains redox balance. Elevated UCP2 expression reduces oxidative stress and protects leukemic cells from apoptosis. Collectively, activation of the CREB–PGC1α–UCP2 axis could contributes to AML progression by promoting mitochondrial fitness, metabolic adaptation, and therapy resistance. Targeting components of this pathway may therefore provide a promising therapeutic strategy for disrupting mitochondrial metabolism and improving treatment outcomes in AML.
Keywords: 
CREB
;  
PGC1α
;  
UCP2
;  
mitochondrial
;  
AML proliferation
;  
metabolism
;  
homeostasis
;  
reprogramming
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology

Introduction

Acute myeloid leukemia (AML) is a biologically aggressive and clinically heterogeneous hematologic malignancy characterized by the uncontrolled proliferation and accumulation of immature myeloid precursor cells, commonly referred to as leukemic blasts, within the bone marrow and peripheral blood [1]. These malignant cells arise from the transformation of hematopoietic stem or progenitor cells and exhibit impaired differentiation, allowing them to expand clonally and disrupt normal hematopoiesis [2]. As leukemic blasts progressively accumulate in the bone marrow niche, they suppress the production of functional erythroid, myeloid, and megakaryocytic lineages, ultimately leading to the characteristic clinical manifestations of AML, including anemia, thrombocytopenia, and neutropenia [3]. The resulting hematopoietic failure contributes to significant morbidity and mortality due to infection, bleeding, and systemic complications associated with marrow failure [2]. The cAMP Response Element Binding protein (CREB)-Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC1α)-Uncoupling Protein 2(UCP2) (CREB-PGC1α-UCP2) signaling axis has emerged as an important regulatory pathway that integrates transcriptional control, mitochondrial metabolism, and cellular stress adaptation in AML. Increasing evidence indicates that leukemic cells rely on coordinated metabolic programs to sustain rapid proliferation, maintain redox balance, and survive under the stressful conditions present within the bone marrow microenvironment [4]. The CREB–PGC1α–UCP2 axis functions as a key regulatory network that links oncogenic signaling to mitochondrial remodeling and metabolic reprogramming, thereby supporting leukemic cell growth and survival.
At the apex of this signaling cascade lies CREB, a transcription factor that serves as an important mediator of cellular responses to diverse extracellular and intracellular stimuli [5] becomes activated through phosphorylation at specific serine residues, most notably Ser133, in response to multiple signaling pathways, including cyclic AMP–dependent protein kinase signaling, mitogen-activated protein kinase pathways, and growth factor–mediated signaling cascades [6]. In AML, aberrant activation of CREB has been frequently observed and has been associated with increased leukemic cell proliferation, impaired differentiation, and resistance to apoptosis. Once activated [7], CREB binds to cAMP response elements located within the promoter regions of target genes and recruits transcriptional co-activators such as CBP and p300, thereby initiating transcriptional programs that regulate cell survival, metabolism, and stress responses [8].
One of the key transcriptional targets influenced by CREB is PGC1α, a master regulator of mitochondrial biogenesis and oxidative metabolism [9]. PGC-1α functions as a transcriptional coactivator that interacts with numerous nuclear receptors and transcription factors to coordinate the expression of genes involved in mitochondrial function, oxidative phosphorylation, fatty acid oxidation, and cellular energy homeostasis [10]. In metabolically active cells, PGC-1α orchestrates mitochondrial biogenesis by activating transcriptional regulators such as nuclear respiratory factors and mitochondrial transcription factor A [10], ultimately leading to increased mitochondrial mass and enhanced oxidative capacity [10]. In AML, elevated PGC-1α expression has been linked to enhanced mitochondrial metabolism and metabolic flexibility, allowing leukemic cells to efficiently adapt to fluctuating nutrient and oxygen availability within the bone marrow niche [11].
Downstream of PGC-1α is the mitochondrial UCP2 which plays a crucial role in fine-tuning mitochondrial bioenergetics and redox balance [12], this UCP2 is located in the inner mitochondrial membrane, where it modulates proton transport across the membrane and influences the coupling efficiency of oxidative phosphorylation [13]. By partially dissipating the proton gradient, UCP2 can reduce mitochondrial membrane potential and limit the excessive generation of reactive oxygen species (ROS) that typically arise during intense mitochondrial respiration [13,14]. In rapidly proliferating leukemic cells, this function is particularly important, as elevated metabolic activity can lead to oxidative stress that threatens cellular viability [15]. Through the regulation of mitochondrial membrane potential and ROS production, UCP2 helps to regulate mitochondrial homeostasis and controls leukemic cells and oxidative damage [13].
The coordinated activity of CREB, PGC-1α, and UCP2 therefore establishes a regulatory axis that links transcriptional signaling to mitochondrial metabolic adaptation. Activation of CREB drives the transcriptional upregulation of PGC-1α, which subsequently promotes mitochondrial biogenesis and metabolic gene expression [9]. PGC-1α-mediated transcriptional programs further enhance the expression of mitochondrial regulators such as UCP2 [12], enabling leukemic cells to optimize mitochondrial efficiency, regulate redox balance, and sustain ATP production under conditions of metabolic stress [13]. This integrated signaling network provides AML cells with the metabolic flexibility required to support continuous proliferation while simultaneously modulating oxidative damage.
Importantly, metabolic reprogramming driven by this axis may also contribute to therapeutic resistance [11]. Many anticancer therapies exert cytotoxic effects through the induction of oxidative stress or disruption of mitochondrial metabolism [16]. By regulating mitochondrial ROS production and maintaining redox homeostasis, UCP2 can attenuate oxidative damage and enhance cellular survival following chemotherapy exposure [13]. Similarly, increased mitochondrial biogenesis mediated by PGC-1α may provide leukemic cells with additional bioenergetic capacity, enabling them to withstand metabolic stress induced by chemotherapeutic agents [11]. Consequently, activation of the CREB–PGC-1α–UCP2 axis may facilitate the persistence of leukemic stem cells and contribute to disease relapse following treatment.
Clinical observations further support the pathological significance of this metabolic signaling axis. Elevated expression levels of PGC-1α and UCP2 have been associated with more aggressive disease phenotypes and unfavorable clinical outcomes in AML patients [12,13]. Increased mitochondrial activity and enhanced oxidative metabolism are frequently observed in leukemic stem cells, which rely heavily on mitochondrial respiration for survival [17]. The CREB–PGC-1α–UCP2 pathway may therefore represent a central mechanism by which leukemic cells sustain mitochondrial function and adapt to metabolic stress within the bone marrow microenvironment.
Given its critical role in regulating mitochondrial metabolism and redox homeostasis, the CREB–PGC-1α–UCP2 axis has attracted growing interest as a potential therapeutic target. Disruption of this pathway could impair mitochondrial adaptation, increase oxidative stress, and sensitize leukemic cells to chemotherapeutic agents [17]. Strategies aimed at inhibiting CREB signaling, suppressing PGC-1α–mediated mitochondrial biogenesis, or modulating UCP2-dependent mitochondrial uncoupling may therefore represent promising approaches for targeting the metabolic vulnerabilities of AML cells. Continued investigation into the molecular regulation of this axis, as well as its interaction with other oncogenic pathways, may provide valuable insights into novel therapeutic strategies aimed at improving clinical outcomes for patients with AML.

Metabolic Reprogramming in AML

Unlike many solid tumors that rely predominantly on aerobic glycolysis (the Warburg effect) [18]. AML cells exhibit a unique metabolic phenotype [19], leukemic blasts and particularly leukemic stem cells (LSCs) [19] display high mitochondrial mass, they depend heavily on oxidative phosphorylation (OXPHOS) that shows metabolic flexibility under therapeutic stress and utilize fatty acid oxidation and amino acid metabolism [20]. This mitochondrial dependency is especially pronounced in chemo resistant AML cells [19]. Residual leukemic cells after chemotherapy often demonstrate an Increased mitochondrial respiration, enhanced reactive oxygen species (ROS) buffering elevated antioxidant capacity and adaptations that support survival under metabolic stress [21]. However, mitochondrial fitness and bioenergetic plasticity are central to AML persistence [20].

Molecular Mechanisms

CREB Signaling and Regulatory Mechanisms

CREB (cAMP Response Element-Binding protein) is a ubiquitous transcription factor that plays a critical role in regulating gene expression in response to diverse intracellular and extracellular signals [22]. It belongs to the basic leucine zipper (bZIP) family of transcription factors and binds specific DNA sequences known as cAMP response elements (CRE) within promoter or enhancer regions of target genes [23]. It plays a crucial role in various cellular processes, including cell proliferation, differentiation, survival, stress and metabolism [8]. It’s a key regulator of gene expression, responding to various signals, including cAMP, calcium, and growth factors [22]. It is evolutionarily conserved and is expressed in nearly all mammalian tissues [8]. Because it integrates multiple signaling pathways into transcriptional responses, CREB acts as a central signaling node linking environmental stimuli to gene regulation [22]. CREB regulates hundreds of genes that control multiple cellular processes. It promotes expression of anti-apoptotic genes such as BCL-2, BCL-XL, MCL-1. [24]. These genes enhance cell survival by preventing programmed cell death [23]. Its regulation of gene involves in cell cycle progression, cyclins as well as growth factor receptors [7]. Through these targets, CREB promotes cell growth and proliferation [8]. In metabolic homeostasis, its regulation of genes involved in glucose and lipid metabolism as well as mitochondrial function [7]. For example, CREB can regulate transcription of PGC-1α [9], a master regulator of mitochondrial metabolism [10] and metabolic proteins like UCP2, through such targets, CREB influences energy production, oxidative metabolism and aadaptive metabolic responses [8]. Furthermore, CREB is frequently overexpressed and constitutively activated in AML. High CREB levels correlate with an increased blast proliferation, an impaired differentiation and poor overall survival [7]. CREB integrates oncogenic signaling pathways such as MAPK and PI3K/AKT and regulates genes involved in cell survival and metabolism [23]. Importantly, CREB also transcriptionally activates metabolic regulators, positioning it as a bridge between oncogenic signaling and mitochondrial function [22].

Regulation of PGC1α Activity and Function

PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator that governs mitochondrial biogenesis, oxidative phosphorylation gene expression, an antioxidant defense programs and, fatty acid oxidation [11]. PGC1α expression are mostly influenced by CREB by binding to cAMP response elements within its promoter. In AML cells, upregulated PGC1α contributes to an increased mitochondrial mass, enhanced respiratory capacity, improved ATP production, adaptation to metabolic stress [25]. It also supports the high-energy demands of proliferating leukemic blasts and provides resilience during chemotherapy [11]. Unlike classical transcription factors, PGC-1α does not bind DNA directly, instead, it interacts with multiple transcription factors and nuclear receptors to enhance their transcriptional activity, thereby coordinating the expression of genes involved in metabolic pathways [12]. PGC-1α expression is highly responsive to environmental and physiological stimuli that affect energy balance [25]. It is metabolically active in tissues such as skeletal muscle, liver, heart, brown adipose tissue, and brain, where energy demand is high [25]. Because of its ability to coordinate metabolic gene networks, PGC-1α is often described as a master regulator of mitochondrial function and oxidative metabolism. It has an RNA-binding domain, suggesting it potential roles in RNA processing and post-transcriptional regulation [11]. In addition, multiple phosphorylation and acetylation sites within PGC-1α regulate its stability and activity in response to cellular signaling pathways [12]. Physical exercise strongly induces PGC-1α expression in skeletal muscle, leading to enhanced mitochondrial biogenesis and improved oxidative capacity [11].
PGC-1α activity is controlled by several upstream signaling pathways including the NAD+-dependent deacetylase Sirtuin 1 activates PGC-1α by removing inhibitory acetyl groups [26], thereby increasing its transcriptional activity and CREB which directly regulates PGC-1α gene expression by binding to the PGC-1α promoter under conditions such as metabolic stress or hormonal signaling [9]. Energy stress activates AMP-activated protein kinase, which phosphorylates and activates PGC-1α [27]. This pathway promotes mitochondrial biogenesis and enhances oxidative metabolism [11]. One of the most important functions of PGC-1α is the regulation of mitochondrial biogenesis and Mitochondrial transcription factor A, which is essential for replication and transcription of mitochondrial DNA [11]. Through these mechanisms, PGC-1α coordinates the expansion of mitochondrial networks and enhances cellular energy production, the process by which new mitochondria are generated within the cell [11,25] PGC-1α activates transcription factors that control mitochondrial gene expression, including nuclear respiratory factor 1 and nuclear respiratory factor 2 [25]. These transcription factors stimulate the expression of genes encoding mitochondrial proteins [12]. Mitochondria generate reactive oxygen species (ROS) during respiration, however PGC-1α helps maintain redox balance by inducing antioxidant genes [11], these include enzymes that detoxify ROS and maintain mitochondrial integrity [12]. PGC-1α may also regulate mitochondrial proteins such as Uncoupling protein 2 (UCP2) [12], which modulate mitochondrial membrane potential and reduce oxidative stress [13].

UCP2 in Pathophysiology

Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier protein family located in the inner mitochondrial membrane [13]. UCP2 belongs to the same family as Uncoupling protein 1 (UCP1), which was originally discovered in brown adipose tissue and is responsible for heat generation through mitochondrial uncoupling [13]. However, unlike UCP1, which functions primarily in thermogenesis, UCP2 is broadly expressed in many tissues including immune cells, liver, pancreas, brain, and hematopoietic cells [28], where it plays important roles in metabolic regulation, mitochondrial function, and cellular stress responses [28]. In physiological conditions, UCP2 regulates mitochondrial efficiency by modulating the coupling between electron transport and ATP synthesis [13]. By allowing protons to re-enter the mitochondrial matrix independently of ATP synthase, UCP2 partially dissipates the mitochondrial proton gradient [13]. This process reduces mitochondrial membrane potential and influences cellular energy metabolism. Although this uncoupling slightly decreases ATP production efficiency, it provides an important mechanism for controlling mitochondrial reactive oxygen species (ROS) generation and maintaining cellular redox balance [28].

Role of UCP2 in Mitochondrial Function

Mitochondria are central to cellular metabolism because they generate ATP through oxidative phosphorylation within the electron transport chain. During this process, electrons pass through mitochondrial complexes, creating a proton gradient across the inner mitochondrial membrane that drives ATP synthesis [28]. However, this process can also produce reactive oxygen species as byproducts. UCP2 modulates mitochondrial activity by reducing proton gradient pressure, thereby limiting excessive ROS production [13]. By lowering mitochondrial membrane potential, UCP2 decreases electron leakage from the respiratory chain, which ultimately reduces oxidative stress [16]. Furthermore, UCP2 acts as a protective regulator of mitochondrial homeostasis, helping cells adapt to metabolic and oxidative stress conditions [29].
Beyond its role in controlling ROS production, UCP2 also influences substrate utilization within the mitochondria [12]. Studies suggest that UCP2 promotes metabolic flexibility by facilitating the transport of certain metabolic intermediates across the mitochondrial membrane [16], this function allows cells to adapt their metabolic pathways in response to changes in nutrient availability or environmental stress.

UCP2 in Oxidative Stress and Redox Homeostasis

Reactive oxygen species are produced during mitochondrial respiration and serve important roles in cellular signaling. However, excessive ROS accumulation can cause oxidative damage to proteins, lipids, and DNA, leading to cellular dysfunction and death [16]. UCP2 contributes to redox regulation by limiting mitochondrial ROS generation [30]. When oxidative stress increases, UCP2 expression is often upregulated as part of a protective cellular response. By dissipating the proton gradient and lowering mitochondrial membrane potential [13], UCP2 reduces electron leakage from the electron transport chain, thereby decreasing ROS formation [12,13]. This antioxidant function of UCP2 is particularly important in AML cells that experience high metabolic activity or oxidative stress [14], such as immune cells and proliferating tissues. Through this mechanism, UCP2 supports cellular survival under stressful conditions.

The CREB–PGC1α–UCP2 Axis in AML: A Mitochondrial Regulatory Circuit

The role of CREB in regulating UCP2 via PGC1α in Acute Myeloid Leukemia (AML) is a complex process. Recent evidence suggests that CREB, a transcription factor that regulates PGC1α [8], in turn modulates UCP2 expression [10], influencing mitochondrial adaptation in AML cells.PGC1α regulates UCP2 expression by acting as a transcriptional coactivator [10]. When activated, PGC1α binds to and coactivates transcription factors like PPARγ (Peroxisome Proliferator-Activated Receptor gamma) and others, which bind to the UCP2 promoter region, enhancing UCP2 transcription [10].
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Figure 1. CREB - PGC1A - UCP2 Metabolic Axis in AM.
Figure 1. CREB - PGC1A - UCP2 Metabolic Axis in AM.
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CREB → PGC1A transcription

CREB binds cAMP-response elements in the PPARGC1A promoter. In AML blasts, constitutive CREB phosphorylation keeps PGC1A transcription high. This is one-way leukemia cells maintain mitochondrial biogenesis without classic driver mutations [10].

PGC1A → UCP2 translation

PGC1α doesn’t bind DNA directly. It coactivates NRF1/NRF2 and ERRα on the UCP2 promoter. Result: increased UCP2 mRNA → UCP2 protein translation. PGC1A is the “driver” of mtDNA copy number in AML, and UCP2 is one of its downstream targets [6].

UCP2 Modulator of Mitochondrial Efficiency and ROS

UCP2 regulates proton gradient dissipation, mitochondrial membrane potential, reactive oxygen species (ROS) levels and, metabolic substrate preference [13]. PGC1α can drive the transcription of UCP2, linking mitochondrial biogenesis to mitochondrial efficiency modulation [14]. Elevated UCP2 expression contributes to reduced mitochondrial ROS accumulation, protection against oxidative stress-induced apoptosis, maintenance of redox balance and, chemoresistance [29]. By fine-tuning ROS production, UCP2 prevents lethal oxidative damage while preserving mitochondrial function a critical survival mechanism in leukemic stem cells [14].

Functional Consequences of the CREB–PGC1α–UCP2 Axis in AML

Redox Homeostasis and Survival

CREB–PGC1α–UCP2 axis collectively promotes mitochondrial expansion and respiratory activity, enabling AML cells to sustain high ATP production, biosynthetic precursor generation and energy-demanding proliferation. Mitochondria play a central role in the regulation of intracellular ROS levels in AML as the primary site of oxidative phosphorylation also, mitochondrial generate ROS as byproducts of electron transport chain activity [31]. Leukemic cells often enhance antioxidant defense mechanisms to counteract this oxidative burden [19]. Key antioxidant systems including glutathione metabolism, thioredoxin pathways, and mitochondrial regulatory proteins are frequently upregulated in AML to maintain redox balance and protect cells from oxidative damage [32]. One important regulator of mitochondrial redox balance is UCP2, it modulates proton leakage across the mitochondrial membrane and reduces mitochondrial ROS production [29]. Elevated expression of UCP2 has been reported in several cancer cells including AML where it contributes to the maintenance of redox homeostasis and promotes leukemic cell survival [14,29]. By limiting excessive ROS accumulation, UCP2 helps protect leukemic cells from oxidative stress [14] induced apoptosis and may contribute to resistance against chemotherapeutic agents that rely on ROS-mediated cytotoxicity [17].
Upstream regulatory pathways also influence redox balance in AML. For example, the transcription factor CREB can regulate metabolic and mitochondrial genes that influence oxidative stress responses [22]. Through transcriptional activation of metabolic coactivators such as PGC-1α, CREB may enhance mitochondrial biogenesis and oxidative metabolism, indirectly influencing ROS production and antioxidant capacity [7]. PGC-1α further coordinates the expression of genes involved in mitochondrial function and oxidative stress defense, thereby supporting cellular adaptation to metabolic and oxidative challenges [11,12].
The ability of AML cells to maintain redox homeostasis provides a significant survival advantage, enabling them to tolerate high metabolic activity and resist apoptosis [19]. Dysregulation of redox regulatory pathways contributes not only to leukemic progression but also to therapeutic resistance [14]. Consequently, targeting redox regulatory mechanisms including mitochondrial ROS control and antioxidant systems has emerged as a promising therapeutic strategy in AML [14]. Disrupting redox balance may sensitize leukemic cells to oxidative stress and enhance the effectiveness of conventional and targeted therapies Chemotherapeutic agents often induce apoptosis via ROS generation [33]. The down regulation of CREB–PGC1α–UCP2 pathway may enhances antioxidant responses and reduces oxidative stress, thereby boosting chemotherapy-induced apoptosis and, disrupt leukemic stem cell maintenance.

AML Mutation Landscape by Biological Process

AML isn’t caused by one mutation. It’s a “multi-step” disease where 2-15 cooperating mutations accumulate in hematopoietic stem/progenitor cells. The 2022 ELN and WHO classifications now group AML largely by genetics. Mutations fall into distinct functional categories that disrupt specific biological processes. Here’s the landscape in detail [34]:
Table 1. CREB, PGC1A, UCP2 in AML - Biological Process, Functional Category, Mechanism, and Mutation/Dysregulation.
Table 1. CREB, PGC1A, UCP2 in AML - Biological Process, Functional Category, Mechanism, and Mutation/Dysregulation.
Gene Biological Process Mechanism in AML Mutation Frequency in AML - COSMIC/Large NGS Specific functions
CREB
(Cyclic AMP Response Element Binding Protein)		 Transcription factor/Signal transduction
Regulates cAMP-dependent gene expression, cell survival, metabolism, angiogenesis.		 CREB is activated by phosphorylation at Ser133 via PKA, MAPK, CaMK. In AML blasts, constitutive CREB activation promotes proliferation, blocks apoptosis, and upregulates oncogenic miRNAs like miR-23a. CREB coactivator CREBBP is fused in t8;16 AML and is a KMT2A partner gene. CREB controls genes involved in metabolism, cell cycle, survival, DNA repair. Not a recurrently mutated driver. No frequency reported in large AML mutation panels. CREBBP fusions are rare: t8;16 KAT6A::CREBBP is included in WHO AML “with other defined genetic alterations” Overexpression/activation, not mutation. CREB is “proto-oncogenic transcription factor” upregulated in AML. CREBBP expression correlates with CEBPA in de novo AML
PGC1A
(PPARGC1A, PGC-1α)		 Mitochondrial biogenesis/Metabolic coactivator
Master regulator of oxidative phosphorylation, mtDNA replication, ROS detox		 PGC1A coactivates NRF1/NRF2 → induces TFAM → increases mtDNA copy number and OXPHOS genes. In AML blasts and stromal cells, PGC1A-driven mitochondrial biogenesis supports leukemia cell survival. PGC1A is upregulated in pediatric AML and higher mtDNA copy number predicts aggressive disease + lower OS. AML stromal cells use PGC1A to regenerate mitochondria transferred to blasts. Eugenol downregulates PGC1A and induces AML apoptosis via mitochondrial pathway Not a recurrently mutated driver. Not listed in AML mutation panels. Study in pediatric AML n=123 shows PGC1A drives mtDNA copy number but mutation frequency not reported Overexpression. “MtDNA copy number is possibly driven by _PGC1A_”. Expression defines subset of tumors with high OXPHOS capacity. Knockdown reduces mtDNA, ATP, respiration
UCP2
(Uncoupling Protein 2)		 Mitochondrial metabolism/ROS regulation
Inner mitochondrial membrane protein, uncouples proton gradient, reduces ROS, supports anabolic metabolism.		 UCP2 exports C4 metabolites/aspartate for NADPH synthesis and glutaminolysis. Overexpressed in leukemia and other cancers → promotes Warburg effect, chemoresistance, tumor growth. Part of SESN1/AMPK/PGC-1α/UCP2 axis: mutant TP53 blocks this axis → increases mitochondrial ROS and proliferation. Context-dependent: can also be tumor-suppressive by reducing ROS. Not a recurrently mutated driver. No mutation frequency reported in AML sequencing studies. Literature focuses on expression, not mutation. Overexpression. “UCP2 is frequently overexpressed in a range of malignancies, including leukemia”. UCP2 deficiency restores chemo sensitivity.
Not mutation-driven genes: CREB, PGC1A, UCP2 don’t show up in AML driver mutation lists like DNMT3A, NPM1, FLT3. Their role in AML is mainly through altered expression, activation, or downstream signaling. Metabolic axis: PGC1A → UCP2 is a functional axis. PGC1A coactivates transcription factors that induce UCP2 expression. Mutant TP53 blocks SESN1/AMPK/PGC1A/UCP2 increases ROS and proliferation. CREB/CREBBP: CREB itself is a transcription factor activated by signaling. CREBBP is a coactivator with HAT activity that gets translocated in rare t8;16 AML. CREB activation is pro-leukemic. Clinical relevance: Because they’re dysregulated, not mutated, targeting is metabolic: eugenol downregulates PGC1A in AML, restoring UCP2 reverses mutant p53 oncogenic effects [34].

Therapeutic Implications

Targeting metabolic vulnerabilities is a promising approach in AML treatment [17], the CREB-PGC1α-UCP2 axis offers multiple potential intervention points, including inhibiting CREB’s transcriptional activity, suppressing PGC1α-mediated mitochondrial biogenesis and targeting UCP2 to disrupt redox adaptation, with combining therapies with OXPHOS inhibitors [14,33]. Therapeutic disruption of this axis may result to distorted mitochondrial fitness, increase ROS accumulation and sensitizing AML cells to chemotherapy thus targeting leukemic stem cell populations. Importantly, because normal hematopoietic stem cells rely less heavily on OXPHOS compared to AML stem cells, metabolic targeting may offer a therapeutic window [19].

Chemoresistance and Relapse

Relapsed AML frequently displays profound metabolic remodeling compared with newly diagnosed disease [19]. Increasing evidence from transcriptomic and metabolic profiling studies indicates that leukemic cells that survive chemotherapy shift toward enhanced mitochondrial respiration and oxidative metabolism [33]. In particular, relapsed AML cells often exhibit increased reliance on Oxidative Phosphorylation (OXPHOS), a metabolic program that allows efficient ATP production and supports long-term survival under therapeutic stress. This metabolic shift reflects a form of adaptive resistance in which leukemic cells remodel mitochondrial function to meet energetic and biosynthetic demands while maintaining redox homeostasis [33].
With evidence from single effect of CREB, PGC1α and UCP2 on AML proved that collectively this signaling axis is a potential important regulatory network coordinating mitochondrial adaptation in AML [9,12].
The transcription factor CREB is frequently activated in leukemia through oncogenic signaling pathways such as MAPK, PI3K/AKT, and cytokine-mediated signaling [8]. The Activation of the CREB–PGC1α pathway in AML can therefore enhance mitochondrial mass and respiratory capacity [9], enabling leukemic cells to sustain high levels of OXPHOS. This metabolic state provides several advantages for leukemic cells exposed to chemotherapy or targeted therapies. Enhanced mitochondrial respiration supports ATP production require for cellular repair processes, drug efflux, and maintenance of cellular homeostasis [17]. Moreover, mitochondrial metabolism generates intermediates necessary for biosynthetic pathways, including nucleotide and amino acid synthesis, which are critical for leukemic cell proliferation and recovery after therapeutic insult [17]. A further downstream component of this axis which is UCP2, can decrease excessive ROS accumulation during periods of heightened mitochondrial activity [13], thereby protecting leukemic cells from oxidative stress induced apoptosis. Chemotherapy, which often induces cytotoxicity through oxidative damage, elevated UCP2 expression may function as a protective mechanism that buffers mitochondrial ROS and preserves mitochondrial integrity [29].
Together, the coordinated activation of CREB, PGC1α, and UCP2 establishes a metabolic circuit that supports mitochondrial flexibility and survival under therapeutic pressure. CREB drives transcriptional activation of mitochondrial regulators, PGC1α enhances mitochondrial biogenesis and respiratory function, and UCP2 mitigates oxidative damage by controlling mitochondrial ROS production [9,13]. This integrated response enables leukemic cells to adapt their metabolic state in response to environmental and pharmacologic stress, facilitating the persistence of minimal residual disease and the emergence of therapy-resistant clones [19].
Importantly, several studies have shown that leukemia stem cells (LSCs), which are thought to drive relapse, are particularly dependent on mitochondrial metabolism and OXPHOS [19]. Unlike bulk leukemic blasts that rely more heavily on glycolysis, LSCs utilize oxidative metabolism to maintain quiescence and long-term survival. Activation of the CREB–PGC1α–UCP2 axis may therefore contribute to the metabolic fitness of LSCs, enabling them to survive initial therapy and later regenerate the leukemic population [7]. This metabolic resilience represents a major obstacle to durable remission in AML.
Furthermore, chemotherapy itself may inadvertently select for cells with higher mitochondrial capacity. Drug-tolerant leukemic cells often show increased expression of mitochondrial genes, enhanced oxygen consumption rates, and upregulation of regulators of oxidative metabolism [35]. CREB-mediated transcriptional activation of PGC1α and UCP2 could act as a metabolic escape mechanism that allows leukemic cells to withstand cytotoxic stress [7,20]. By sustaining mitochondrial function and controlling oxidative damage, this signaling axis may supports cellular adaptation during treatment, ultimately promoting disease recurrence.
From a therapeutic perspective, targeting components of this metabolic pathway represents a promising strategy to overcome relapse. Inhibiting CREB activation could disrupt the transcriptional program driving mitochondrial remodeling [7]. Alternatively, targeting mitochondrial metabolism directly such as through OXPHOS inhibitors may selectively impair leukemic cells that rely on oxidative metabolism for survival. Similarly, modulating UCP2 activity may increase mitochondrial ROS accumulation, sensitizing leukemic cells to chemotherapy-induced oxidative damage [31].
Taken together, the CREB–PGC1α–UCP2 signaling network can be conceptualized as a metabolic survival module in AML by coordinating mitochondrial biogenesis, oxidative metabolism, and redox balance, this axis equips leukemic cells with the metabolic flexibility required to endure therapeutic stress. In relapsed AML where mitochondrial dependence is often heightened, activation of this pathway may facilitate the persistence of resistant leukemic clones and drive disease recurrence. Consequently, a deeper understanding of the molecular mechanisms governing this axis may reveal new opportunities for therapeutic intervention aimed at disrupting metabolic adaptations that sustain AML relapse.

Conclusion

Mitochondria play a pivotal role in AML biology by serving not only as energy-producing organelles but also as key regulators of redox signaling, apoptosis, and metabolic flexibility [36]. Leukemic cells frequently exhibit enhanced mitochondrial biogenesis and increased reliance on oxidative phosphorylation (OXPHOS) to meet the high energetic and biosynthetic demands associated with rapid proliferation [19]. This mitochondrial dependency distinguishes many AML cells from normal hematopoietic cells and represents a critical vulnerability that can potentially be exploited therapeutically. Among the regulatory pathways that coordinate mitochondrial metabolism in AML, the signaling axis involving CREB, PGC-1α and UCP2 [12] has emerged as an important mediator of mitochondrial adaptation. CREB is frequently overexpressed or constitutively activated in AML, regulates genes involved in cell survival, proliferation, and metabolic control [7]. Through transcriptional activation of PGC-1α, it promotes mitochondrial biogenesis and enhances oxidative metabolism [9]. PGC-1α, in turn, acts as a master coactivator that orchestrates the expression of numerous mitochondrial genes involved in oxidative phosphorylation and metabolic homeostasis [10].
A key downstream effector of this pathway is UCP2 modulates mitochondrial membrane potential and regulates the production of reactive oxygen species (ROS) [13]. By reducing excessive ROS accumulation, UCP2 helps maintain intracellular redox balance and protects leukemic cells from oxidative stress induced apoptosis [14]. This regulation of redox homeostasis is particularly important for AML cells, which often experience elevated oxidative stress due to their high metabolic activity [14]. By buffering ROS levels, the CREB–PGC1α–UCP2 axis might allow leukemic cells to maintain mitochondrial efficiency while avoiding oxidative damage.
Collectively, this coordinated regulatory network might enhances mitochondrial biogenesis, optimizes oxidative phosphorylation, and preserves redox balance within leukemic cells. These adaptations will infuse AML cells with remarkable bioenergetic flexibility, enabling them to thrive in metabolically challenging environments and resist the cytotoxic effects of chemotherapy. Consequently, activation of the CREB–PGC1α–UCP2 axis could contributes to leukemic cell proliferation, long-term survival, and therapy resistance.
Given the central role of each of CREB, PGC1α and UCP2 in regulating mitochondrial metabolism and redox homeostasis, focused investigation of the CREB–PGC1α–UCP2 signaling pathway may reveal previously unrecognized metabolic vulnerabilities in AML. Targeting components of this mitochondrial regulatory axis could disrupt leukemic energy metabolism, increase oxidative stress, and sensitize AML cells to existing therapies. As such, this pathway represents a promising avenue for the development of novel metabolism-based therapeutic strategies aimed at improving clinical outcomes for patients with AML.
In this review, we summarized the pivotal roles of CREB, PGC1α and UCP2 within AML and discussed various factors that interact with or participate in the multi-level regulation of CREB, PGC1α and UCP2 in the AML. A comprehensive understanding of the functions of CREB, PGC1α and UCP2 would serve as the basis for further research and potentially pave the way for novel strategies in AML treatment.

Authorship Contribution statement

Agida Okohi Innocent wrote the manuscript and made the literature selection; Sun Ruixin made the literature selection; Li Yongqi made the literature selection; Jinke Cheng revised the manuscript; Jiao Ma revised the manuscript.

Declarations: Declaration of Generative AI and AI-assisted technologies in the writing process

Author declares that no generative AI and AI assisted technologies was applied in writing this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82370186), and the Natural Science Foundation of Shanghai (No.23ZR1436100).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 82370186) and the Natural Science Foundation of Shanghai (No. 23ZR1436100).

Conflicts of Interest

The authors declare no competing interests. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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