Hypoxia-inducible factor-1α/β-catenin axis: A conserved regulatory hub for enhancing stem cell function in tissue regeneration

Abstract

This article provides an in-depth commentary on the study by Wang et al, which elucidates that the hypoxia-inducible factor-1α (HIF-1α)/β-catenin axis serves as a core hub regulating the function of peripheral blood mesenchymal stem cells (PBMSCs) under hypoxic conditions. The research confirms that in a hypoxic environment, HIF-1α acts as an upstream regulator by directly binding to and activating the transcription of β-catenin, a relationship that is unidirectional and irreversible. This axis enhances the therapeutic potential of PBMSCs through a dual mechanism: On one hand, it regulates anti-apoptotic proteins while inhibiting pro-apoptotic molecules, significantly improving cell survival and self-renewal capacity; on the other hand, it promotes the secretion of factors such as vascular endothelial growth factor, thereby enhancing angiogenic activity. In a rat myocardial infarction model, PBMSCs overexpressing HIF-1α showed significantly improved retention in the infarcted area, reduced infarct size, and promoted neovascularization - effects that were abolished upon knockdown of β-catenin. This discovery provides a key target for optimizing stem cell therapy for myocardial infarction. By pre-activating this axis in vitro (e.g., via lentiviral vectors or small-molecule regulators), it is possible to standardize and enhance the survival and reparative capacity of PBMSCs in ischemic tissues, holding important translational medical value.

Key Words: Hypoxia-inducible factor-1α; β-catenin; Stem cell; Tissue regeneration; Conserved regulatory hub

Core Tip: The hypoxia-inducible factor-1α/β-catenin axis functions as a conserved regulatory hub that enhances stem cell survival and angiogenic capacity under hypoxic conditions. This unidirectional signaling pathway, with hypoxia-inducible factor-1α as the upstream driver, coordinates anti-apoptotic and pro-angiogenic responses in stem cells, offering a promising target for improving cell-based therapies in ischemic diseases such as myocardial infarction.

This editorial refers to “HIF-1α modulates β-catenin pathway to enhance the survival and angiogenesis of PBMSCs under hypoxia environment” by Wang et al, 2025; https://doi.org/10.4252/wjsc.v17.i11.112484.

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INTRODUCTION

Regeneration refers to the precise regrowth of cells, tissues, or organs following injury, aiming to restore their original structure and function[1]. The capacity for regeneration varies significantly across different species in nature, and in humans, it is limited to certain cells and tissues. Hypoxia constitutes a crucial microenvironmental signal in both embryonic development and tissue regeneration. However, the mechanisms underlying its interaction with the core regulatory factor hypoxia-inducible factor-1α (HIF-1α) in determining stem cell fate remain debated. A study on mouse embryonic stem cells revealed that hypoxia strongly suppresses mesoderm and endoderm differentiation by inhibiting the Wnt/β-catenin signaling pathway. Surprisingly, HIF-1α does not simply mediate the hypoxic effect in this process but instead assumes the role of a “fine-tuner” - it intrinsically enhances the Wnt/β-catenin pathway and promotes mesoderm differentiation, thereby partially counteracting the inhibitory effect of hypoxia[2]. This suggests that HIF-1α and Wnt/β-catenin form a regulatory hub that is likely highly conserved in development and regeneration. Mounting evidence indicates that HIF-1α and β-catenin signaling do not operate in isolation but engage in extensive and profound crosstalk at transcriptional, protein stability, and functional levels, forming a sophisticated regulatory hub[3]. Wang et al[4] conducted relevant research on the HIF-1α/β-catenin axis as a highly conserved regulatory hub for enhancing stem cell function during tissue regeneration.

THE MOLECULAR INTERFACE OF HIF-1Α AND Β-CATENIN SIGNALING

Interaction between HIF-1α and β-catenin under hypoxic conditions

In the hypoxic tumor microenvironment, HIF-1α and the β-catenin signaling pathway form a closely interconnected and cancer type-specific regulatory network. In hepatocellular carcinoma, studies have shown that the natural compound bruceine D targets the β-catenin/T-cell factor inhibitor, promotes β-catenin degradation, and thereby suppresses the expression of downstream HIF-1α and metabolic reprogramming, revealing an upstream regulatory role of β-catenin over HIF-1α[5]. In contrast, in breast cancer, hypoxia-induced HIF-1α directly negatively regulates the transcriptional repressor MBP1, relieving its suppression on β-catenin gene transcription and subsequently activating the Wnt/β-catenin pathway, indicating that HIF-1α acts upstream of β-catenin in this model[6]. In gastric cancer[7], a third mode has been identified: Hypoxia-upregulated A-kinase-interacting protein 1 simultaneously activates both HIF-1α and β-catenin signaling, jointly promoting tumor invasion and stem-like properties. Together, these studies demonstrate that the relationship between HIF-1α and β-catenin is not a simple unidirectional regulation, but rather a dynamic network characterized by crosstalk, directional flexibility, and modulation by specific upstream molecules. Its precise regulatory logic is highly dependent on tumor type and microenvironmental context.

Haroon and Kang[8] aimed to elucidate the multi-pathway inhibitory effects of the natural flavonoid kaempferol on colon cancer under hypoxic conditions, with the core mechanism involving the simultaneous targeting of two critical signaling axes: HIF-1α/vascular endothelial growth factor and Wnt/β-catenin. In this study, a CoCl₂-induced hypoxic colon cancer cell model was employed. Cell viability, proliferation, and migration were assessed through MTT, clonogenic, wound healing, and Transwell assays. The expression and activity of key proteins and genes were analyzed using techniques such as western blot, quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter gene assays. The results demonstrated that kaempferol effectively inhibited the stabilization of HIF-1α protein and its downstream angiogenic targets, while concurrently downregulating β-catenin and key components of its signaling pathway, thereby synergistically suppressing angiogenesis and the epithelial-mesenchymal transition process. Furthermore, kaempferol promoted cancer cell apoptosis by inducing reactive oxygen species (ROS) generation, causing DNA damage, modulating the mitogen-activated protein kinases/protein kinase B (Akt) pathway, and activating the caspase cascade. HIF-1α plays a crucial role in stabilizing β-catenin, particularly under hypoxic conditions, thereby amplifying Wnt signaling. In glioblastoma, hypoxia significantly enhances HIF-1α expression, which in turn activates the Wnt pathway by stabilizing β-catenin[9].

The impact of sustained hypoxia on Wnt/β-catenin signaling in germ layer differentiation

In the field of embryonic development, Shen et al[10] revealed an unexpected antagonistic relationship between hypoxia and HIF-1α in regulating fate decisions in mouse embryonic stem cells. Their study found that hypoxia suppresses Wnt/β-catenin signaling by inhibiting the Akt/glycogen synthase kinase-3β axis, thereby restraining mesendodermal differentiation and promoting ectodermal differentiation. In contrast, however, HIF-1α overexpression enhanced Wnt/β-catenin pathway activity and promoted mesendodermal differentiation. Crucially, the inhibitory effect of hypoxia persisted in HIF-1α-knockdown cells, demonstrating that this effect is HIF-1α-independent. Further transcriptomic analysis indicated that HIF-1α acts more selectively, functioning to fine-tune the overall impact of hypoxia on cell differentiation. This work challenges the conventional view of HIF-1α merely as a mediator of hypoxic effects, establishes the Wnt/β-catenin pathway as a common yet inversely regulated downstream hub, and provides a new paradigm for understanding the complex regulatory mechanisms of the hypoxic environment in development. Conversely, Hong et al[11] demonstrated that in lung adenocarcinoma, hypoxia stabilizes HIF-2α rather than HIF-1α, activating the phosphoinositide 3-kinase/Akt pathway, which subsequently promotes β-catenin accumulation and nuclear translocation, thereby enhancing Wnt signaling activity. This mechanism significantly increases tumor cell migration, invasion, and resistance to prolonged hypoxic stress, highlighting the critical role of the HIF-2α/β-catenin axis in the malignant progression of lung cancer and offering a new potential target for therapies aimed at the hypoxic tumor microenvironment.

The interaction between HIF-1α and β-catenin under different hypoxic contexts

In the acute hypoxic microenvironment following ischemic stroke, the expression of HIF-1α is typically induced, but the sustained activation of its downstream pro-repair signals may be insufficient. The study by Hu et al[12] provides a novel regulatory perspective on this issue. They found that in a rat MCAO model, delayed hyperbaric oxygen therapy initiated during the subacute phase significantly up-regulated HIF-1α expression not by prolonging hypoxia, but by inducing ROS generation. The activated HIF-1α further served as a crucial upstream signal, driving the activation of the canonical Wnt/β-catenin pathway, as evidenced by increased expression of β-catenin and its downstream targets lymphoid enhancer factor-1 and T-cell factor-1. The activation of this signaling axis ultimately up-regulated the expression of the neurogenesis core regulator neurogenin-1, as well as the maturation markers doublecortin (DCX) and synapsin-1, thereby significantly promoting hippocampal neurogenesis and improving neurological functional recovery during the chronic phase of stroke. It is noteworthy that inhibiting either ROS or HIF-1α completely blocked the pro-neurogenic effects of hyperbaric oxygen, which directly corroborates the central mediatory role of the “ROS/HIF-1α/β-catenin” cascade in this process[12]. Studies on chronic hypoxia have shown that the hypoxic microenvironment stabilizes HIF-1α, which directly activates the hypoxia-responsive elements in the hepatitis B virus (HBV) genome, enhancing viral transcription and replication. Concurrently, single-cell transcriptomic analysis revealed that β-catenin (encoded by CTNNB1) expression was significantly up-regulated in the same hypoxic regions. The known Wnt/β-catenin signaling pathway has also been reported to positively regulate HBV replication. Although the study did not explicitly elucidate a direct interaction between HIF-1α and β-catenin, their spatial co-expression in hypoxic areas suggests they may function cooperatively within the same microenvironment, creating a multi-factorial synergistic state that promotes viral replication. This finding indicates that in the chronically hypoxic centrilobular zone (zone 3) of the liver, HIF-1α and β-catenin together constitute a synergistic regulatory network that promotes HBV replication[13]. This study, exploring the mechanisms by which obstructive sleep apnea syndrome (OSAS)-related intermittent hypoxia (IH) promotes colorectal cancer, offers a new perspective on the relationship between hypoxia and the HIF-1α/β-catenin pathway. The research demonstrated that under IH conditions mimicking OSAS, HIF-1α expression was significantly activated in pre-cancerous colon epithelial cells, an effect similar to that of sustained hypoxia. However, unlike findings from many sustained hypoxia studies, this study found that while IH up-regulated β-catenin mRNA levels, it did not trigger the translocation of β-catenin protein into the nucleus, suggesting that the canonical Wnt/β-catenin pathway was not genuinely activated in this model. This result implies that under the OSAS-specific IH mode, the up-regulation of HIF-1α may not directly drive carcinogenesis by stabilizing β-catenin. Instead, it may shift to activate other oncogenic pathways (such as signal transducer and activator of transcription 3), thereby revealing that IH may involve different molecular mechanisms affecting key signaling networks in colorectal cancer compared to sustained hypoxia[14] as shown in Table 1.

Table 1 Hypoxia-inducible factor-1α and β-catenin under different hypoxic contexts.

Hypoxia model/biological context	Acute hypoxia (post-stroke recovery)	Chronic hypoxia (liver HBV replication)	Intermittent hypoxia (OSAS promotes cancer)
HIF-1α status	Significantly upregulated by delayed HBO via ROS induction	Stably highly expressed due to direct hypoxic stabilization	Markedly activated under IH conditions
β-catenin pathway status	Significantly activated (↑ protein expression & nuclear translocation)	Co-activated (↑ expression, functional synergy with HIF-1α)	Not truly activated (↑ mRNA, but no nuclear translocation)
Core regulatory mechanism	Forms a sequential ROS → HIF-1α → β-catenin signaling cascade	HIF-1α and β-catenin show spatial co-expression and functional synergy	HIF-1α activation is decoupled from the canonical Wnt/β-catenin pathway
Primary functional outcome	Promotes neurogenesis and improves neurological recovery	Synergistically promotes HBV transcription and replication	Promotes colorectal carcinogenesis (likely via alternative pathways, e.g., STAT3)

HBV: Hepatitis B virus; OSAS: Obstructive sleep apnea syndrome; HIF-1α: Hypoxia-inducible factor-1α; HBO: Hyperbaric oxygen; ROS: Reactive oxygen species; IH: Intermittent hypoxia; STAT3: Signal transducer and activator of transcription 3.

STEM CELLS AND REGENERATION

In the field of tissue regeneration and stem cell research, age-related decline in regenerative capacity is a central issue. The perspective article by Birch and Gil[15] in 2020 reviews the key study by Ritschka et al[16], which revealed the important role of cellular senescence in restricting liver regeneration in adult mammals. The study found that after partial hepatectomy in adult mice, a subset of hepatocytes abnormally and persistently overexpress the cell cycle inhibitor p21, entering a “pre-senescent” state accompanied by a SASP-like inflammatory response, thereby impeding the regeneration process. Notably, intervention with the senolytic drug ABT-737 restored regenerative capacity in the adult liver not by eliminating classical senescent cells, but by specifically downregulating p21 expression and improving the regenerative microenvironment. This work emphasizes that moving beyond the classical stem cell proliferation paradigm and targeting the senescent state of mature somatic cells (such as hepatocytes) represents a novel and promising strategy for promoting endogenous tissue regeneration. Woodworth et al[17] systematically reviewed endogenous progenitor-based neuronal regeneration strategies in the mammalian retina. The study highlights Müller glia as a potential stem cell source, which can be reprogrammed to transdifferentiate into various retinal neuronal types upon induction by transcription factors (e.g., Ascl1, Atoh1). However, low regenerative efficiency and incomplete differentiation remain major bottlenecks. By comparing highly regenerative species such as zebrafish and chickens, the researchers identified the role of inhibitory factors like NFI in suppressing mammalian regeneration and emphasized the critical importance of single-cell transcriptomic analysis in validating the authenticity of regeneration. This review provides a theoretical foundation and an experimental framework for achieving tissue-specific neuroregeneration using endogenous stem cells, underscoring the convergent potential of gene therapy and developmental biology in regenerative medicine. In recent years, hydroxyapatite (HAp)-based biomaterials have gained increasing prominence in bone tissue engineering due to their high similarity to the inorganic component of natural bone. Studies have shown that HAp not only serves as a scaffold material to support stem cell adhesion and differentiation but also indirectly influences stem cell behavior and bone regeneration processes by modulating the immune microenvironment, particularly through macrophage polarization[18]. By optimizing physicochemical properties - such as size, morphology, and surface modification - and incorporating bioactive components, HAp can shape an osteo-friendly immune microenvironment, thereby enhancing stem cell-mediated tissue repair and regeneration. Therefore, an in-depth exploration of the immunomodulatory functions of HAp will provide a critical theoretical foundation for developing regenerative strategies based on stem cell-biomaterial synergy[19]. It is noteworthy that, according to the latest authoritative International Delphi Consensus, mesenchymal stromal cells are defined as a standard umbrella term based on minimal phenotypic criteria (e.g., CD73+/CD90+/CD105+ and CD45-) and tissue of origin. In contrast, the term mesenchymal stem cells specifically refers to a functional subset within mesenchymal stromal cells that has been experimentally demonstrated to possess stemness, including self-renewal and multilineage differentiation potential. These two terms are not synonymous: While all mesenchymal stem cells belong to the category of mesenchymal stromal cells, the reverse is not true. The use of “mesenchymal stem cells” must be supported by corresponding evidence of stemness; otherwise, the term “mesenchymal stromal cells” should be consistently applied to ensure terminological accuracy and comparability across studies. In this article, the term “mesenchymal stromal cell” refers specifically to mesenchymal stem cells[20].

THE ROLE OF THE HIF-1Α/Β-CATENIN AXIS IN STEM CELLS AND REGENERATION

Recent studies have revealed that HIF-1α signaling plays a critical role in stem cell self-renewal, differentiation, and tissue regeneration. In mouse embryonic stem cells, HIF-1α exhibits a dynamic “bind-release-bind” pattern on chromatin during the transition from normoxia to stable hypoxia, with its strongest binding under stable hypoxia correlating with the regulation of genes essential for maintaining pluripotency[2]. This regulatory function is not isolated; it intersects with other critical pathways. For instance, the interaction between HIF-1α and β-catenin is vital, as their competition for binding to ten-eleven translocated methylcytosine dioxygenase 1 can influence downstream signaling relevant to stem cell state[21]. Furthermore, the SET domain family of methyltransferases can modulate the activity of pathways like Wnt/β-catenin and HIF-1α through epigenetic modifications, thereby influencing the transcriptional programs that govern the stem cell niche and pluripotency[22]. This intricate crosstalk ensures the maintenance of a stem cell pool capable of both self-renewal and differentiation. Wan et al[23] demonstrated that the Chinese herbal compound Qigu capsule significantly suppresses oxidative stress-induced senescence in mesenchymal stem cells and promotes their osteogenic differentiation by activating the HIF-1α/AMP-activated protein kinase axis, thereby improving bone microarchitecture and mechanical properties in an osteoporosis model. Their findings suggest that beyond its role in hypoxia adaptation, HIF-1α also regulates stem cell fate and regenerative potential through crosstalk with metabolic pathways such as AMP-activated protein kinase. Although this study did not directly address β-catenin, existing literature indicates functional crosstalk between HIF-1α and the Wnt/β-catenin pathway in bone formation. Future research should further explore the synergistic mechanisms of the HIF-1α/β-catenin axis in stem cell-mediated bone regeneration. The HIF-1α/β-catenin signaling axis plays a central role in regulating stem cell self-renewal and tissue regeneration. Liu et al[24] revealed in a breast cancer study that under hypoxic conditions, HIF-1 transcriptionally upregulates CALR expression, which in turn activates the Wnt/β-catenin pathway, thereby promoting the maintenance and enhancement of breast cancer stem cell properties. This mechanism not only drives tumor initiation, metastasis, and chemotherapy resistance but also highlights how HIF-1α, by regulating downstream target genes such as CALR, indirectly amplifies β-catenin signaling to remodel stem cell fate under pathological conditions. This finding provides key experimental evidence for understanding the dual role of the HIF-1α/β-catenin axis - participating in physiological tissue repair while also driving pathological stem cell expansion - in stem cell homeostasis and regeneration, offering new perspectives for targeting this axis in regenerative medicine and anti-cancer strategies. Within the complex network of HIF-1α-mediated regulation of stem cell fate, its synergistic interplay with the autophagy pathway is increasingly gaining attention, offering new insights into stem cell survival under stressful microenvironments. A study on intervertebral disc regeneration provides compelling evidence: It found that in degenerated discs, the expression of HIF-1α is significantly reduced, which closely correlates with the apoptosis and depletion of endogenous nucleus pulposus stem cells (NPSCs). Experiments in vitro mimicking the harsh disc microenvironment - characterized by both hypoxia and abnormal mechanical loading - the stable expression of HIF-1α proved essential for NPSC survival[25]. The core mechanism lies in the fact that HIF-1α does not act in isolation; instead, it initiates the HIF1A-BNIP3-ATG7 signaling axis, markedly upregulating cellular autophagic activity. This enhanced autophagic flux clears accumulated cellular damage, thereby effectively counteracting mitochondrial pathway-mediated apoptosis. More importantly, genetically engineered NPSCs overexpressing HIF-1α demonstrated significantly improved survival and tissue repair potential after being transplanted into compressed degenerated discs. This study reveals that within mechanically sensitive stem cell niches, HIF-1α serves as a central hub in maintaining stem cell pool stability and ensuring regenerative efficacy by precisely regulating autophagy - a critical quality control mechanism. These findings suggest that when investigating the crosstalk between HIF-1α and canonical signaling pathways such as β-catenin, autophagy may represent an indispensable node and synergistic effector.

THE CONSERVATION OF THE HIF-1Α/Β-CATENIN AXIS

Recent studies have gradually revealed that within the regulatory networks governing stem cell fate determination, there exist upstream epigenetic “checkpoints” capable of integrating multiple key signaling pathways, thereby forming conserved regulatory hubs. Among these, the histone demethylase LSD1 plays a particularly prominent role[26]. It is noteworthy that LSD1 has been found to govern both HIF-1α and β-catenin - two transcriptional regulators critical for development and regeneration - through a similar molecular mechanism. In the hypoxic response, LSD1 modulates osteoclastogenesis by regulating HIF-1α[27]. In a parallel discovery, research on muscle and embryonic stem cells has revealed another conserved mechanism: LSD1 can directly bind to and demethylate β-catenin at lysine 180 (K180). This modification event represents more than mere signaling crosstalk; rather, it establishes a critical intranuclear “checkpoint” within the Wnt/β-catenin pathway - effectively preventing the degradation of nuclear β-catenin, thereby maintaining its appropriate protein levels and transcriptional activity. Functionally, this axis is essential for the proper orientation of the mitotic spindle and for asymmetric stem cell division directed by Wnt3A signaling. Loss of LSD1 impairs the nuclear function of β-catenin, skewing stem cell division toward symmetric self-renewal and consequently expanding the stem cell reservoir during tissue regeneration. This indicates that LSD1 acts as a common upstream epigenetic regulator, which, through direct demethylation and stabilization of both HIF-1α and β-catenin, constitutes a conserved regulatory hub that transcends cell types and signaling pathways, precisely orchestrating stem cell fate decisions in response to microenvironmental cues such as hypoxia and Wnt[28]. HIF-1α and β-catenin function as two central signaling hubs governing stem cell fate, exhibiting remarkable context-dependent functionality. In physiological regeneration, such as in radiation-induced intestinal injury, the small molecule Me6TREN promotes the phosphorylation and nuclear translocation of β-catenin by activating the phosphoinositide 3-kinase/Akt and extracellular signal-regulated kinase pathways, thereby driving the proliferation of Lgr5+ intestinal stem cells and crypt regeneration to accomplish tissue repair[29]. In stark contrast, under pathological conditions like lenvatinib resistance in hepatocellular carcinoma, phosphorylated MYH9 recruits the deubiquitinase USP22 to aberrantly stabilize HIF-1α protein under normoxia, consequently enhancing cancer stem cell traits and leading to therapy resistance[30]. These two studies highlight, from the dimensions of ‘activating proliferation’ and ‘maintaining stemness’ respectively, the core mechanism of precisely regulating transcription factor stability to determine stem cell fate. It is noteworthy that the HIF-1α and β-catenin pathways do not operate in isolation; extensive crosstalk exists between them, potentially forming positive feedback loops in pathological states such as cancer, thereby cooperatively sustaining the malignant phenotype of stem cells. Similar to the eIF3a-YY1-β-catenin axis revealed in our study, HIF-1α, stabilized within hypoxic stem cell niches (e.g., in regenerating tissues or tumor stem cell niches), has also been found to influence the activity and nuclear localization of β-catenin through direct or indirect transcriptional regulation. The underlying mechanisms may include the functional association of HIF-1α with the β-catenin/T-cell factor complex at target gene promoters, co-activating gene programs related to stemness maintenance and proliferation (such as c-MYC and CCND1)[31]. Furthermore, investigating how specific factors (e.g., YY1) integrate HIF-1α signaling to precisely regulate the transcriptional level of β-catenin provides a fresh perspective for understanding the fine-tuned regulation of stem cell fate during tissue regeneration. Therefore, in-depth dissection of the HIF-1α/β-catenin axis not only holds significant implications for regenerative medicine but also offers potential novel strategies for targeting cancer stem cells.

FUTURE CHALLENGES AND DIRECTIONS

Despite the promising prospects, translating these findings into clinical applications presents several challenges. Foremost, whether this regulatory mechanism is similarly conserved in adult stem cells across various tissues (e.g., neural, muscular, hepatic) requires extensive validation. Furthermore, the precise molecular connections between the HIF-1α and Wnt pathways remain to be elucidated - specifically, whether they interact directly or through intermediary factors. Ultimately, a core challenge in drug development and therapeutic strategy is achieving spatiotemporally precise modulation of this axis within the complex in vivo environment.

CONCLUSION

In the fields of stem cell biology and tissue regeneration, the crosstalk between the HIF-1α and β-catenin signaling pathways constitutes a critical regulatory axis. As emphasized in this commentary, the Wnt/β-catenin pathway itself is a master regulator governing stem cell maintenance, cell fate determination, and tissue regeneration. Within hypoxic stem cell niches - such as those in regenerating tissues or tumor stem cell niches - the stabilized HIF-1α protein demonstrates profound synergy with β-catenin signaling. On one hand, HIF-1α can influence β-catenin’s activity and nuclear localization through direct or indirect transcriptional regulation, thereby mimicking or amplifying Wnt signaling and co-activating target gene programs (e.g., c-MYC, CCND1) associated with cell proliferation and stemness maintenance. On the other hand, the coordinated activation of the HIF-1α/β-catenin axis is crucial in physiological processes like skeletal muscle regeneration, liver repair, and the hair follicle cycle, where it activates resident stem cells and promotes progenitor expansion and lineage-specific differentiation. However, persistent dysregulation of this axis is also intimately linked to pathological fibrosis and the maintenance of cancer stem cell properties. Therefore, a deeper dissection of how HIF-1α precisely modulates β-catenin signaling not only provides novel insights into the regulatory mechanisms of tissue regeneration and stem cell fate but also lays a theoretical foundation for developing new regenerative medicine strategies aimed at either promoting tissue repair by targeting this axis or eradicating cancer stem cells.