Targeting the CTRP3-PTEN-PI3K/AKT axis in diabetic wound repair: Implications for keratinocyte resilience

Abstract

Diabetes mellitus is associated with impaired wound healing and delayed re-epithelialization, which remain major clinical challenges in diabetic care. Recent findings published in the World Journal of Diabetes by He et al suggest that CTRP3 may contribute to diabetic wound repair by regulating keratinocyte function through the PTEN-PI3K/AKT signaling pathway. Their study showed that CTRP3 expression is reduced under diabetic or high-glucose conditions and increases during normal wound healing. CTRP3 supplementation promoted keratinocyte proliferation, migration, and angiogenic signaling, partly through PTEN suppression and subsequent PI3K/AKT activation. However, the association between CTRP3 and PTEN should be interpreted cautiously, because current evidence does not yet prove a direct, exclusive, or fully validated linear pathway. Further studies using PTEN silencing, PTEN rescue experiments, PI3K/AKT inhibition, time-resolved in vivo wound-tissue validation, and safety-focused human-relevant models will be necessary before CTRP3-based therapeutic strategies can be considered for clinical application.

Key Words: CTRP3; Diabetic wound healing; Keratinocytes; PTEN; PI3K/AKT signaling; Angiogenesis

Core Tip: Diabetic wound healing is severely impaired by metabolic dysregulation, chronic inflammation, and defective keratinocyte function. Emerging evidence highlights CTRP3 as a metabolically responsive adipokine with regenerative potential. Recent experimental findings indicate that CTRP3 promotes keratinocyte proliferation, migration, and angiogenic signaling while suppressing PTEN to activate the PI3K/AKT pathway. This editorial discusses how the CTRP3-PTEN-PI3K/AKT axis integrates metabolic signaling with epithelial repair processes and may represent a promising molecular target for improving diabetic wound healing outcomes.

This editorial refers to “C1q tumor necrosis factor associated protein 3 protects HaCaT via phosphoinositide 3-kinase/protein kinase B activation by PTEN reduction” by He et al, 2026; https://dx.doi.org/10.4239/wjd.v17.i4.114061.

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INTRODUCTION

The healing of diabetes-related wounds is a growing global health challenge and is presently growing with the increase in the number of people suffering from diabetes and its associated adverse outcomes. Foot ulcers in individuals with diabetes number around 18.6 million globally, resulting in high rates of infections, hospitalizations, amputations and 5-year mortality similar to many cancers[1,2]. Uncontrolled blood sugar levels interfere with the tightly-coordinated processes (or phases) of tissue repair because of impaired formation of new blood vessels (angiogenesis), prolonged inflammatory response, and damage to blood vessels with inflammation (microvascular disease)[3-5]. Furthermore, keratinocyte dysfunction-evidenced by altered keratinocyte proliferation and migration, keratinocyte differentiation, and keratinocyte-mediated immune response-has been identified as a critical contributor to delayed re-epithelialization in chronic diabetic wounds[6,7]. Together, these metabolic, vascular and epithelial abnormalities highlight the importance of elucidating the intracellular signalling pathways that mediate hyperglycaemia-induced cellular stress signalling and pro-repair signals.

The signalling pathway that appears to play the most important role in the regulation of cell survival, angiogenesis and the transition of macrophage phenotype during the repair of diabetic wounds is the PI3K/AKT signaling pathway. Preclinical studies have consistently demonstrated that activation of the PI3K/AKT pathway leads to enhanced wound closure and blood vessel growth (angiogenesis) in conditions of hyperglycaemia; however, the activity of negative upstream regulators of the PI3K/AKT pathway, such as PTEN, inhibits pro-repair signalling[8-11]. The increasing recognition of adipokines as systemic mediators bridging the gap between metabolic homeostasis, inflammation, and tissue repair is occurring concurrently to their recognition as systemic mediators. CTRP3 has also been shown to positively contribute to insulin sensitivity, and to the anti-inflammation effects[12,13]. Decreased levels of CTRP3 in circulation are observed in patients with diabetes and the complications associated with diabetes[14,15]. In the latest issue of the World Journal of Diabetes, He et al[16] present evidence from different types of clinical diagnoses that show CTRP3 is integrated into the already established PI3K/AKT-PTEN signaling pathway and contributes to healing of diabetic wounds.

In this study, He et al[16] utilize an in vivo diabetic wound model of the db/db mouse along with HaCaT keratinocytes to determine how CTRP3 modulates the repair of epithelial tissue under conditions of hyperglycemia. They have established that CTRP3 is expressed at lower levels in keratinocytes that have been exposed to high glucose than in returning to normal levels of expression is once an epithelial wound heals; therefore, CTRP3 addition will lead to the restoration of keratinocyte proliferation and migration while upregulating the VEGF protein. As has been demonstrated in previous studies of acute wound healing in db/db diabetic mice, administration of CTRP3 to db/db diabetic mice has accelerated the speed of wound closure and improved the histological characteristics of healing. The authors provide evidence that CTRP3’s pro-reparative properties are due in part to the activation of PI3K/AKT signaling through the reduction of PTEN. Additionally, however, they also show that PTEN overexpression diminishes or negates the CTRP3-driven pro-reparative phenotypes produced in the HAcat cells. Overall, these studies suggest that CTRP3 may function as an upstream, metabolism-sensitive regulator and can reduce the inhibitor threshold on the canonical pro-survival pathway within the healing of full-thickness diabetic wounds[16].

KEY CONCEPTUAL CONTRIBUTION OF THE STUDY

Consequently, the main conceptual contribution of this research is the more detailed identification of the upstream regulation of a previously established reparative signaling axis. Activation of the PI3K/AKT pathway has been well-established to enhance angiogenesis, promote keratinocyte survival, and facilitate macrophage phenotype transition in the process of diabetic wound repair[9-11,17]. Nevertheless, there has not been any extensive definition of which upstream metabolic regulators can modulate PI3K/AKT activity in diabetic keratinocytes. Previous studies have determined that PTEN is a potent negative regulator of this pathway through its role as a lipid phosphatase that discourages PI3K activity and therefore diminishes regenerative responses[11]. By revealing CTRP3 as a putative antagonist of PTEN expression, the current study addresses a fundamental mechanistic gap related to how a metabolically regulated adipokine might relieve the inhibitory pressure on PI3K/AKT activity in the microenvironment surrounding a diabetic wound.

CTRP3-PTEN association established by using co-immunoprecipitation (Co-IP) lends additional mechanistic insight to support the deeper mechanistic dimension of this study. However, it is critical to carefully interpret this evidence. Co-IP provides confirmation of protein-protein interaction under laboratory conditions but fails to provide conclusive evidence of direct binding affinity, structural specificity, or dynamic regulation in vivo. Functional studies whereby increased expression of PTEN reverses CTRP3-induced activation of the PI3K/AKT pathway as well as inhibits keratinocyte proliferation and migration provide strong additional corroborating evidence; however, these findings remain pathophysiology based rather than structurally based. Collectively, these data support the idea of a functional CTRP3-PTEN regulatory component; however, additional biochemical characterization will be necessary to determine if this interaction is direct or indirect, or can vary depending on the context[16].

The most significant outstanding question is whether or not CTRP3 regulates PI3K/AKT signaling via PTEN exclusively or whether PTEN is just one of several components in a larger signaling network. Although the current data support the functional relationship between CTRP3, PTEN, and PI3K/AKT activation, they do not provide conclusive evidence that this pathway is a linear and direct pathway, or that this pathway is an exclusive pathway. Future studies should evaluate the role CTRP3 Loss-of-function, PTEN silencing or knockdown, PTEN rescue experiments, and pharmacological inhibitors of PI3K/AKT in CTRP3-dependent keratinocyte proliferation and migration are dependent on PTEN and PI3K/AKT. Therefore, the CTRP3-PTEN-PI3K/AKT axis should be viewed as a proposed mechanistic framework, not a fully validated signal transduction pathway. This interpretation is particularly important because PTEN may represent only one component of a broader CTRP3-regulated network. CTRP3 could also influence other inflammatory, metabolic, angiogenic, or redox-sensitive pathways that converge on keratinocyte survival and migration. Therefore, the current evidence supports a functional association between CTRP3, PTEN reduction, and PI3K/AKT activation, but it does not establish PTEN as the sole mediator of CTRP3-dependent wound repair. From a mechanistic standpoint, the existence of a true CTRP3-PTEN-PI3K/AKT signaling axis requires more than correlative changes in PTEN expression and PI3K/AKT activation. Future studies should directly test whether CTRP3-mediated activation of PI3K/AKT is lost after PTEN silencing or knockdown, whether PTEN rescue reverses the effects of CTRP3, and whether pharmacological inhibition of PI3K/AKT abolishes CTRP3-induced keratinocyte proliferation, migration, and pro-angiogenic factor expression. Such experiments would help distinguish whether PTEN is an obligatory mediator of CTRP3 activity or one regulatory node within a broader CTRP3-sensitive signaling network.

The combination of db/db diabetic mice in vivo with HaCaT keratinocytes treated with high glucose in vitro provides a translationally relevant biological model for this project. db/db mice represent systemic metabolic dysfunction and delayed wound healing, which are characteristic of type 2 diabetes. High glucose-treated HaCaT keratinocytes allow examination of the cellular response to hyperglycemia and thus enhance the biological relevance of the overall model. However, immortalized keratinocytes cannot replicate the full extent of the diabetic wound microenvironment, where fibroblasts, endothelial cells, macrophages, and the extracellular matrix will communicate temporally over time[3,4]. For this reason, while the two model systems provide stronger mechanistic correlation, they do not represent conclusive preclinical evidence. In human diabetic foot ulcers, keratinocyte behavior is shaped by continuous interactions with fibroblasts, endothelial cells, macrophages, immune mediators, extracellular matrix remodeling, microbial burden, ischemia, and persistent hyperglycemia. For this reason, findings obtained in HaCaT keratinocytes should be considered mechanistic and hypothesis-generating rather than fully representative of the diabetic foot ulcer microenvironment.

The finding provided by He et al[16] provides novel information about CTRP3’s role as a regulator of epithelial tissue repair due to its enhanced ability to regulate keratinocyte cell behavior and wound healing dynamics. CTRP3 enhances insulin sensitivity and the inflammatory balance as well as being decreased in concentration in people with diabetes and its complications[12-15]. The study transitions CTRP3 from an established systemic adipokine that regulates glucose and fatty acid metabolism to a localized regulator of epithelial wound healing, thereby creating a new link between adipokine biology and regenerative dermatology, and establishing a new area of overlap between endocrine signaling and tissue regeneration.

The present study does not provide the basis for a novel signaling cascade but rather uses a well-established signaling cascade, the PTEN-PI3K/AKT axis, to create a new biological paradigm. The primary contribution of this study is the placing of CTRP3 within the PTEN-PI3K/AKT regulatory axis during the healing of diabetic wounds. Therefore, although the present study does not redefine the basic signaling paradigm, it does refine understanding of metabolic regulation of epithelial tissue repair.

CLINICAL AND TRANSLATIONAL IMPLICATIONS

The translational value of He et al’s findings[16] should be assessed regarding the ongoing gap in therapy available for the treatment of diabetic foot wounds. Diabetic foot ulcers have high risks of developing infection, hospitalization, amputation, and prolonged mortality, despite the use of structured multidisciplinary care, indicating that there is a gap in therapy for the management of diabetic foot ulcers beyond traditional treatment for the wound surface[1,2,18-20]. Conventional interventions (e.g., offloading, advanced dressings) mainly target the biomechanical and local conditions of the wound and fail to correct the defect in intracellular pro-survival and pro-angiogenic signaling that sustain chronic wound tissue due to hyperglycemic conditions[21]. In this light, manipulating intracellular regulatory nodes (e.g., PTEN) represents an alternative to traditional therapy.

PTEN has been established as a master regulator of cell proliferation, survival, and genomic stability[22]. Caution should be utilized with any therapeutic approaches designed to inhibit or decrease PTEN activity; this is due to PTEN being a tumor suppressor. Although there may be a theoretical benefit to transient or spatially restricted modulation of PTEN in injured tissue in response to therapies aimed at promoting regeneration without introducing cancer risk through systemic exposure, prior studies have shown that PTEN’s inhibition specifically in tissue with injury promotes regeneration when the effects of this translationally potent precursor (a.k.a., angiogenin) (PI3K/AKT signaling) has been manipulated in a location- and time-dependent manner in various models of skin and vascular repair without causing cancer[9,23,24]. Therefore, the potential translational viability of CTRP3-based therapeutic approaches is dependent on utilizing controlled and localized delivery systems.

In order to minimize oncogenic risk, any CTRP3-targeted therapeutic approach should avoid sustained or systemic inhibition of PTEN. This point is critical because PTEN is a major tumor suppressor with essential roles in genomic stability, cell-cycle control, and the prevention of uncontrolled PI3K/AKT pathway activation. Therefore, the therapeutic goal should not be broad PTEN suppression, but rather transient, localized, and reversible modulation of impaired regenerative signaling within the wound bed. A safer translational strategy may require local delivery to the ulcer site, short-term exposure during the active phase of re-epithelialization, careful dose titration to restore rather than overactivate PI3K/AKT signaling, and biomaterial-based systems that limit diffusion beyond injured tissue. Safety assessments should include markers of keratinocyte overproliferation, abnormal epidermal thickening, dysplastic changes, persistent AKT/mTOR activation, and delayed recovery of PTEN activity after wound closure. Several practical strategies may reduce oncogenic risk in future CTRP3-based interventions. First, CTRP3 delivery should preferably be restricted to the wound bed rather than administered systemically. Second, exposure should be time-limited and aligned with the active re-epithelialization phase, with discontinuation after wound closure. Third, dose-escalation studies should define the minimum effective dose required to restore impaired PI3K/AKT signaling without producing sustained pathway overactivation. Fourth, local biomaterial-based delivery systems, such as degradable hydrogels, nanoparticles, or wound dressings, may help limit diffusion into non-injured tissues. Fifth, preclinical safety testing should include long-term surveillance for epidermal hyperplasia, dysplasia, abnormal keratinocyte proliferation, persistent AKT/mTOR activation, and delayed restoration of PTEN activity. These safeguards would be essential before considering clinical translation of any intervention that indirectly or directly modulates PTEN activity.

Emerging biomaterials platforms have further supported the concept of incorporating CTRP3 into such platforms where it can spatially modulate and activate PI3K/AKT signaling while minimizing overall systemic inhibition of PTEN[25,26]. This strategy is consistent with a current regenerative medicine paradigm that favours the recalibration of microenvironmental pathways above the global pharmacologic activation of pathways.

In addition to potential therapeutic implications, CTRP3 is likely to have biomarker applications. Diabetes results in circulation of lower levels of CTRP3, which is also negatively associated with various markers of metabolic dysfunction and inflammatory burden[14,15]. If longitudinal studies identify that CTRP3 levels correlate with severity of wounds, trajectory of healing, or risk of recurrence, then CTRP3 could be utilized to stratify patients for personalized wound care management. Integrating metabolic biomarkers into the principles of regenerative medicine is consistent with the larger precision medicine effort currently occurring in diabetes care.

Translational research from this study must overcome critical barriers to be translated into clinical practice. These barriers include the need to validate the effects of CTRP3 on primary human keratinocytes, confirm effects in large animal diabetic wound models, characterize how CTRP3 is delivered pharmacokinetically, and evaluate the safety of modulating PTEN. Therefore, while the present study does not support clinical application of CTRP3, it does provide a mechanistic basis for rational development of targeted regenerative medicine.

In conclusion, while the findings of He et al[16] do not yet change clinical practice, they provide a basis for developing a mechanistic model in which adipokine function and intracellular regenerative signaling converge. The true translational impact of this work hinges on future research investigating appropriateness of dosage, specificity of tissue targeted, safety for induced tumor growth, and the method of delivery. If these challenges are overcome, there is a possibility that the modulation of the CTRP3-PTEN-PI3K/AKT pathway could provide an additional biological treatment for diabetic ulcers which would support but not replace current methods of treatment.

LIMITATIONS AND FUTURE DIRECTIONS

The research offers important mechanistic understanding of the CTRP3-PTEN-PI3K/AKT pathway through diabetic wound healing, but there are several theoretical, and methodological points to consider. To start, diabetic wounds exhibit a varied network of cells, with chronic inflammation, dysfunctional cells of the immune system, dysfunction of the endothelium, and an unorganized extracellular matrix all playing key roles in the healing process[21]. The use of single cell transcriptomics has identified an extremely heterogeneous population of keratinocytes and immune cells in diabetic wounds and shows that epithelial cell signaling alone cannot explain the entire response. As such, while HaCaT cell systems can provide helpful mechanistic information, they cannot reproduce the dynamic pathways of one cell type influencing another that are seen in human chronic wounds[27-29].

The addition of db/db diabetic mice improved the physiological relevance but the mechanistic evidence is better characterized in HaCaT keratinocytes treated with high glucose than in wound tissue. To gain in vivo proof of the CTRP3-PTEN-PI3K/AKT sequence, future studies should assess CTRP3, PTEN, phosphorylated PI3K/AKT, as well as keratinocyte proliferation, angiogenesis and modification from inflammation within the wound over time. Building upon this, appropriate assessment of the specific pathways that the manipulation of CTRP3 or PTEN will have on epithelial-autonomous effects or systemic endocrine or immune-mediated effects can be performed through conditional or wound-specific manipulation of the above genes. Ultimately, the currently available in vivo information supports the existence of a biological plausibility but not definitive mechanistic validation. Although the db/db mouse wound model provides useful in vivo relevance, the current evidence does not yet demonstrate the complete CTRP3-PTEN-PI3K/AKT sequence within wound tissue itself. In particular, temporal in vivo confirmation is needed to show that CTRP3 administration first reduces PTEN activity or expression in the wound bed, subsequently restores PI3K/AKT phosphorylation, and then leads to measurable improvements in keratinocyte proliferation, re-epithelialization, angiogenesis, and inflammatory resolution. Without such time-resolved wound-tissue evidence, the mechanism demonstrated in HaCaT keratinocytes should be considered biologically plausible but not definitively validated in vivo.

Second, manipulating PTEN signaling raises new safety issues. A loss-of-function mutation of the PTEN gene is a key genomic gatekeeper to the integrity of DNA and as a genomic gatekeeper, the deletion of PTEN via mutation is implicated as a potential oncogenic event due to the role of PTEN as a critical gatekeeper for the EGFR pathway as there have been numerous studies linking EGFR/PI3K/AKT pathway activation in leading to various cancers[24]. Furthermore, studies show that the activity of PI3K/AKT pathway is constantly activated when PTEN function is partially inhibited[30]. Consequently, the long-term or systemic inhibition of PTEN function raises potential concerns about its oncogenic risk. Subsequent studies should carefully examine the dose response, reversibility, and tissue distribution of CTRP3-mediated PTEN inhibition in long-term in vivo studies. Longitudinal clinical studies are also needed to determine whether circulating or local wound-bed CTRP3 levels can predict the healing trajectory of diabetic foot ulcers. Such studies should evaluate whether baseline CTRP3 levels, temporal changes during treatment, or CTRP3 responses after debridement and standard wound care are associated with wound closure, recurrence, infection risk, or need for amputation. This would clarify whether CTRP3 has potential not only as a therapeutic target but also as a prognostic biomarker in diabetic foot ulcer management.

Third, chronic diabetic ulceration is associated with key aspects of metabolic memory and oxidative/reductive imbalance as they relate to epigenetic reprogramming of mitochondrial dysfunction[31]. It remains unclear if CTRP3 could be exerting influence outside of PTEN protein loss. A better understanding of the potential mechanisms by which CTRP3 modulates rates of transcriptional, epigenetic, or redox-mediated pathways may greatly add to our understanding of the mechanisms underlying chronic diabetic ulceration. Additionally, numerous mechanisms of diabetes-related regulation of PTEN may also interact with the regulation of PTEN via CTRP3 signaling. For example, gene expression for PTEN is regulated via microRNAs and other non-coding RNAs and therefore PTEN gene expression can lead to alterations in the pathways via which PI3K and AKT promote cellular proliferation, migration and angiogenesis during wound healing or the resolution of inflammation. In addition to regulating PTEN protein function, the presence of oxidative/reductive imbalance may also influence the activity of PTEN, through the modulation of post-translational modifications of PTEN, due to their redox sensitivity. Thus, any of the above mechanisms of regulation may lead to CTRP3-mediated PTEN inhibition being enhanced, diminished, masked by, or in competition with other regulatory mechanisms. Further investigational endeavors are warranted to determine if CTRP3 plays a role in these mechanisms, either through the activation of these potential properties, or if it is only involved in specific metabolic and/or inflammatory conditions. These alternative regulatory mechanisms are especially relevant in diabetes, where hyperglycemia-induced oxidative stress, mitochondrial dysfunction, advanced glycation end-products, inflammatory cytokines, and non-coding RNA networks may independently alter PTEN abundance, localization, oxidation state, or phosphatase activity. MicroRNAs and other non-coding RNAs may suppress or enhance PTEN expression at the post-transcriptional level, whereas redox imbalance may modify PTEN activity through oxidation-sensitive conformational changes. These mechanisms could either amplify, attenuate, or obscure the apparent effect of CTRP3 on PTEN and PI3K/AKT signaling. Therefore, future studies should determine whether CTRP3 acts upstream of these PTEN-regulatory mechanisms, interacts with them, or functions through parallel pathways that converge on PI3K/AKT activation.

Furthermore, this experiment employed a loss-of-function methodology to determine if CTRP3 provides the necessary role in the process of epithelial repair or is sufficient to be involved in the process. Additionally, the method of action for CTRP3 at both the level of the wound and potentially by systemic means via the regulation of the endocrine system or immune modulation requires further tissue specific assessment.

Looking ahead, validation of CTRP3 in primary human diabetic keratinocytes, organotypic skin equivalents, and large-animal diabetic wound models would strengthen the translational relevance of future studies. Biochemical analyses of how CTRP3 regulates PTEN by way of post-translational modification via changing ubiquitin, proteasomal degradation, or stabilization through phosphorylation remains a major priority for future research. Last, incorporation of CTRP3 into spatially localized biomaterial delivery systems will potentially provide a means of exploiting regenerative properties while sparing the systemic tumour suppressor functions attributed to PTEN.

CONCLUSION

The process of diabetic wound healing is inherently biologically complex due to multiple overlapping biological processes involved in the mechanism of tissue regeneration, including metabolic dysregulation; chronic cellular inflammation; and microcirculatory dysfunction and epithelial barrier disruption[21]. The PI3K/AKT signalling pathway is a key regulator of cell survival, angiogenesis and regenerative capacity in the context of this landscape[30]. PTEN, a master tumour suppressor and an important regulator of genomic stability, places tight constraints on this process, with dysregulation of PTEN strongly associated with oncogenesis. The resulting interplay between regenerative activation and tumour surveillance represents a key element of biological tension that is created by modulating the therapeutic pathway[24].

He et al[16] have refined rather than redefined the current paradigm of diabetic wound signalling within this mechanistic context. By inserting CTRP3 into the PTEN-PI3K/AKT regulatory framework, this publication provides a metabolically driven perspective on the control of epithelial repair. The conceptual contribution of this study is to identify a systemic adipokine as a putative modulator of intracellular inhibitory thresholds within the diabetic wound microenvironment.

Whether CTRP3 will become a clinically relevant therapeutic target or remain a mechanistic bridge between metabolic biology and regenerative biology will depend on future validation. At present, the CTRP3-PTEN-PI3K/AKT axis should be regarded as a promising but not yet conclusive therapeutic framework. If the CTRP3-PTEN association is confirmed in primary human cells, organotypic skin models, and clinically relevant diabetic wound systems, and if safety barriers related to PTEN modulation are overcome, this axis could become a biologically rational target for diabetic foot ulcer treatment. Until then, CTRP3 should be viewed as a candidate regulator of diabetic wound repair rather than a validated clinical intervention. Mechanistic confirmation using PTEN loss- and gain-of-function approaches, PI3K/AKT pathway inhibition, and longitudinal in vivo wound-tissue analyses will be required to determine whether CTRP3 truly operates through a defined CTRP3-PTEN-PI3K/AKT axis or through a broader network of PTEN-dependent and PTEN-independent mechanisms.