The Mechanistic Role of PPARγ in Wound Healing

Abstract

The receptor known as peroxisome proliferator‐activated receptor gamma (PPARγ) is crucial for effective wound healing, and recent progress has given a deeper understanding of its complex functions. As a biological switch, PPARγ regulates the immune response by shifting macrophages from promoting inflammation to supporting tissue regeneration, while suppressing pro‐inflammatory signals to create an ideal healing environment. At the cellular level, PPARγ enhances the migration of keratinocytes and promotes re‐epithelialization, thereby accelerating the wound closure process. It also promotes the differentiation of preadipocytes and the formation of new blood vessels, making a significant contribution to tissue regeneration. At the molecular level, PPARγ plays a dual role in guiding epithelial–mesenchymal transformation to aid healing while preventing excessive scarring. It improves mitochondrial efficiency to provide the energy needed for tissue repair. Despite these promising mechanisms, the clinical use of current PPARγ agonists faces hurdles due to side effects and regulatory hurdles. Moving forward, research should aim to develop targeted delivery methods, tailor therapies to individual needs, and investigate how PPARγ interacts synergistically with other signaling pathways, all of which are essential steps toward translating these findings into clinical practice.

1. Introduction

Wound healing represents a sophisticated biological cascade that coordinates multiple cellular and molecular events to restore tissue integrity following injury. This meticulously orchestrated process—spanning inflammatory control, cellular regeneration, blood vessel formation, and extracellular matrix (ECM) reorganization—determines the functional recovery of damaged tissue. While superficial wounds generally follow an efficient, self‐regulated healing trajectory, more severe injuries caused by major trauma, systemic diseases like diabetes, or persistent infections often face complications such as impaired healing and excessive scarring. These issues not only compromise the skin’s protective function but may also result in cosmetic concerns and physical limitations, dramatically affecting patients’ wellbeing [1, 2]. Consequently, unraveling the molecular drivers of wound repair and discovering therapeutic avenues to optimize this process remain key priorities in both trauma care and regenerative medicine.

PPARγ, a key player in the nuclear receptor family, was first identified for its central role in fat cell development and metabolic balance. However, subsequent research has revealed its far‐reaching influence across diverse biological functions, from immune modulation and cell specialization to tissue regeneration. Emerging evidence highlights PPARγ’s critical role in wound healing [3, 4]: it fine‐tunes the inflammatory response by steering macrophages toward a healing phenotype [5], accelerates wound closure by boosting keratinocyte movement and skin layer renewal [6], promotes tissue rebuilding by stimulating fat cell maturation [7] and blood vessel growth [8], and dynamically regulates epithelial–mesenchymal transition (EMT) [9] to balance repair and scarring [10]. These findings position PPARγ as a multifaceted regulator of wound healing, offering promising theoretical support for novel therapeutic approaches.

The activity of PPARγ is complex and context‐dependent, shaped by factors such as ligand binding, cell type, and environmental cues. It can trigger gene expression through direct DNA interaction after forming a heterodimer with RXR and binding to PPREs [11] or indirectly influence signaling pathways (e.g., NF‐κB and STAT6) to modulate inflammation and metabolism [12]. Although traditional PPARγ activators like thiazolidinediones (TZDs) [13, 14] have shown potential, their clinical use is hampered by adverse effects, including cardiovascular risks and metabolic disturbances. This underscores the importance of refining PPARγ‐targeted therapies through deeper mechanistic insights.

This review synthesizes current knowledge on PPARγ’s role in wound healing, detailing its regulatory effects on immune cells, skin cells, fat cells, and blood vessel linings. It also explores its interplay with inflammatory signals, metabolic pathways, and scar formation. By evaluating both the opportunities and challenges in clinical translation, this work aims to provide a robust scientific framework for developing PPARγ‐based interventions in wound management.

2. The Wound Healing Process

Wound healing progresses through sequential, overlapping phases: inflammation, proliferation, and remodeling. Briefly, upon injury, hemostasis and inflammation initiate the process, involving platelet aggregation and neutrophil infiltration for debris clearance. The proliferative phase is characterized by fibroblast activation, ECM deposition, angiogenesis, and re‐epithelialization. Finally, the remodeling phase involves ECM maturation and scar formation. PPARγ exerts regulatory functions across all these stages, as detailed in the following sections [15, 16].

3. Distribution and Physiological Significance of PPARγ in Skin Organs

3.1. Overview of the Structure, Ligands, and Functions of PPARγ

In the 1960s, researchers initially observed that the lipid‐lowering medication clofibrate could prompt an abnormal proliferation of peroxisomes, which are organelles involved in lipid oxidation, in the livers of rats. Various compounds, including fatty acids and fibrate lipid‐lowering drugs, can elicit similar effects and are collectively known as “peroxisome proliferators” (PP). In 1990, British scientists Issemann and Green isolated a novel nuclear receptor protein from mouse livers that could be selectively activated by PP [17]. This protein was termed peroxisome proliferator‐activated receptor (PPAR). Three subtypes of PPAR have been recognized: PPARα (NR1C1), PPARδ/β (NR1C2), and PPARγ (NR1C3). As a member of the nuclear receptor superfamily, PPAR is a transcription factor that modulates gene expression upon ligand activation, regulating genes responsible for metabolic balance and diverse organ functions [18, 19]. PPARγ is predominantly expressed in the immune system, adipose tissue, duodenum, and proximal colon, and is the most extensively studied subtype within the PPAR family. The human PPARγ gene is situated in the 3p24.2‐p25 region of chromosome 3 and comprises nine exons [20]. Because of variances in promoters and alternative splicing, two isoforms of PPARγ exist: PPARγ1, expressed widely in various tissues (including white and brown adipose tissues, the immune system, liver, and muscle) and PPARγ2, exclusive to adipose tissue, featuring an additional 28–30 amino acids at its N‐terminus compared to PPARγ1 [21]. The structure of the PPARγ protein is evolutionarily conserved, with the DNA‐binding ability concentrated in the highly conserved C domain [22].

PPARs modulate gene transcription via ligand‐induced conformational changes, forming heterodimers with retinoic X receptors to bind PPAR response elements [23]. Upon ligand binding, coactivators are recruited to initiate target gene expression. For instance, PPARγ activation by fatty acid derivatives enhances lipid breakdown, while TZD drugs induce adipocyte differentiation [11, 24, 25]. Conversely, antagonists recruit corepressors to impede transcription. Some ligands can also elicit effects via PPAR‐independent pathways; for example, 15‐deoxy‐Δ12,14‐prostaglandin D2 inhibits nuclear factor κB activity [26]. Phosphorylation, in addition to binding to response elements, modulates PPAR activity. Various kinases (e.g., MAPK, PKC, PKA) influence PPAR function through phosphorylation, with outcomes contingent upon multiple factors such as stimulus type, kinase involved, PPAR subtype, modified residue, cell type, and target gene promoter. The interplay of ligand binding and kinase‐mediated phosphorylation finely tunes PPAR activity [27, 28], integrating lipid and cell membrane signals to precisely regulate target genes in diverse physiological contexts through subtype‐specific modifications.

3.2. Distribution and Function of PPARγ in Skin Tissue

In humans, PPARγ demonstrates pronounced expression predominance in various tissues, notably white adipose tissue, colon, spleen, lymphoid tissue, and bone marrow [29, 30]. Additionally, notable expression is observed in the kidneys (particularly in the medullary collecting ducts and papillary urothelial cells), heart, small intestine, ovaries, testes, liver, bladder (transitional epithelial cells), and epidermal keratinocytes [6, 31, 32]. PPARγ1 exhibits widespread expression in human tissues, particularly in macrophage lines and monocytes, where it plays a pivotal role in regulating genes associated with lipid metabolism and inflammatory responses [33]. Moreover, it is present in aortic and coronary artery smooth muscle cells, endothelial cells, and skeletal muscle [34]. The relative expression levels of PPARγ1 and γ2 in adipose tissue vary among individuals and can be modulated by dietary factors. While adipocytes display similar responses in insulin sensitivity and gene expression profiles upon activation of either PPARγ1 or γ2, PPARγ2 demonstrates greater potency in inducing adipogenesis at lower ligand concentrations [35]. Furthermore, the distinct tissue distribution of the two isoforms, coupled with variations in their ratio, implies that their expression levels may be modulated by specific disease conditions or reflect the activation or deactivation of PPARγ during disease progression [36].

The epidermis, the outermost layer of the skin, is a multilayered epithelium crucial for protecting against microbial, mechanical, and chemical threats. Keratinocytes, originating in the basal layer, undergo a sophisticated differentiation process as they migrate towards the stratum corneum. This process involves biochemical modifications, expression of structural proteins, and lipid processing reorganization, culminating in the formation of the hydrophobic stratum corneum. PPARγ, present in various skin cell types, exhibits widespread expression in the skin [37, 38]. Its expression peaks during late embryonic development but declines postnatally [30, 32, 39, 40]. In adult skin, PPARα and PPARγ exhibit relatively low expression levels, while PPARβ is predominant. Despite lower expression levels in the dermis compared with the epidermis, PPARα, β, and γ are also present in the dermis [19, 41]. PPARγ plays a critical role in regulating the skin barrier by inhibiting the expression of pro‐inflammatory genes through antagonizing inflammatory transcription factors NF‐κB and AP‐1 [40, 42].

PPARγ is predominantly localized in keratinocytes within the skin [6, 41], with its expression increasing as keratinocytes transition from the basal to the granular layer [28]. In vitro studies have demonstrated that PPARγ agonists can upregulate genes associated with keratinocyte differentiation [6, 42]. Immunohistochemical analysis reveals nuclear localization of PPARγ, with variations in staining intensity observed among different cell types [28]. Positive staining for PPARγ is also evident in the epidermis, the cytoplasm of the inner root sheath of hair follicles, sebaceous glands [43, 44], human melanocytes, and adipocytes within subcutaneous adipose tissue.

PPARγ plays a pivotal role in preserving the structural and functional integrity of the skin by orchestrating multiple key processes [45, 46]. It facilitates the differentiation of epidermal keratinocytes, leading to the synthesis of essential structural proteins (e.g., loricrin, filaggrin) and barrier lipids (e.g., ceramides, cholesterol). This culminates in the formation of a robust cornified envelope and the secretion of lamellar bodies, crucial for establishing and maintaining the skin’s vital physical barrier, which effectively shields against water loss and external insults. Additionally, PPARγ drives sebocyte differentiation and sebum production, essential for sebaceous gland function in skin moisturization and surface antibacterial defense, while also playing a role in regulating the hair follicle cycle.

In terms of immune modulation, PPARγ exerts potent anti‐inflammatory effects by suppressing the production of pro‐inflammatory factors by keratinocytes and immune cells, as well as modulating immune cell functions to prevent exaggerated inflammatory responses. Furthermore, PPARγ can enhance the skin’s resilience to oxidative stress induced by environmental factors like ultraviolet radiation by upregulating the expression of antioxidant enzymes. As a central regulatory node, PPARγ is indispensable for maintaining overall skin homeostasis by comprehensively regulating barrier function, appendage activities, immune equilibrium, regenerative capacity, and antioxidant defenses. Dysregulation of PPARγ is closely linked to the pathogenesis of various skin disorders.

Furthermore, the activation of PPARγ plays a crucial role in orchestrating the wound‐healing process following skin injury. It enhances re‐epithelialization through promoting keratinocyte migration and proliferation, regulates ECM synthesis by fibroblasts, exerts moderate control over inflammation, and stimulates angiogenesis.

4. Mechanisms by Which PPARγ Promotes Wound Healing

4.1. PPARγ Affects Wound Healing by Regulating Immunity

4.1.1. Anti‐Inflammatory Mechanism of PPARγ During the Wound Healing Process

PPARγ expression is dynamically regulated during wound repair (Figure 1). Its levels decrease initially post‐injury but significantly increase during the late repair stage, coinciding with a shift in lipid mediators from pro‐inflammatory prostaglandin E2 (PGE2) to anti‐inflammatory prostaglandin D2 (PGD2) and its metabolite 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), which serves as an endogenous PPARγ ligand [47, 48]. This temporal association suggests a role for the PGD2/15d‐PGJ2‐PPARγ axis in inflammation resolution.

Figure 1.

Anti‐inflammatory mechanisms of PPARγ in wound healing. During the inflammatory phase, wound stimuli (TNFα/IL‐18/LPS) activate endothelial adhesion molecules (VCAM‐1/ICAMs), facilitating leukocyte infiltration and inflammatory amplification. In the repair phase, lipid metabolism shifts from PGE₂ to PPARγ ligands (PGD₂/15d‐PGJ₂). Insulin/P38‐mediated dephosphorylation (Ser112) activates PPARγ, which suppresses inflammation through: (1) CREB coactivator competition; (2) p65/p50 DNA‐binding blockade; (3) NCoR complex recruitment to inhibit NF‐ κ B; and (4) AP‐1 signal inhibition. This downregulates adhesion molecules, chemokines (CCL2/CXCL10), and inflammatory mediators (TNFα/IL‐6/MMPs), ultimately reducing leukocyte infiltration, promoting M1 → M2 macrophage transition, and resolving inflammation for tissue repair.

PPARγ activation suppresses the expression of endothelial adhesion molecules (e.g., VCAM‐1) and chemokines (e.g., CCL2, CXCL10), thereby inhibiting leukocyte recruitment to the wound site [49, 50]. This anti‐inflammatory effect is mediated through multiple mechanisms, including: Transrepression of NF‐κB and AP‐1: PPARγ can directly interact with these pro‐inflammatory transcription factors or prevent the dissociation of corepressor complexes (e.g., NCoR), thereby suppressing the expression of their target genes [50, 51]. Ligand‐dependent mechanisms: Natural (e.g., 15d‐PGJ2) and synthetic (e.g., TZDs) PPARγ ligands exert potent anti‐inflammatory effects in wounds, reducing pro‐inflammatory cytokines (TNF‐α, IL‐1β, IL‐6) and elevating anti‐inflammatory IL‐10. These effects are often reversible by PPARγ antagonists like GW9662, confirming receptor specificity [52, 53].

4.1.2. Regulatory Effect of PPARγ on Immune Cells During Wound Healing

PPARγ modulates the function of various immune cells to fine‐tune the wound immune landscape.

Dendritic cells (DCs): PPARγ activation impairs DC maturation, reduces the expression of co‐stimulatory molecules (CD80, CD83) and IL‐12 secretion, thereby attenuating their antigen‐presenting capacity and subsequent T cell activation [54, 55].

T cells: PPARγ activation in T cells suppresses the production of pro‐inflammatory cytokines like IFNγ (Th1) and IL‐17 (Th17), while promoting the differentiation and function of regulatory T cells (Tregs) [56, 57].

Mast cells and ILC2s: PPARγ suppresses IgE‐mediated mast cell degranulation and inflammatory cytokine release [58]. It also inhibits the IL‐33‐driven production of IL‐5 and IL‐13 by group 2 innate lymphoid cells (ILC2s), curbing Th2‐type inflammation [59].

Monocytes/macrophages: (Discussed in detail in Section 4.1.3).

4.1.3. Effects of PPARγ on Macrophages

Macrophages are pivotal in wound healing, undergoing a phenotypic switch from pro‐inflammatory M1 to pro‐repair M2 states (Figure 2). PPARγ is a master regulator of this M2 polarization [52, 60]. Drivers of M2 polarization: The IL‐4/IL‐13/STAT6 signaling pathway is a key inducer of PPARγ expression in macrophages. PPARγ, in turn, sustains the M2 phenotype and drives the expression of characteristic M2 markers like Arg1 and CD206 [61, 62]. Metabolic reprogramming: PPARγ activation promotes fatty acid β‐oxidation and mitochondrial biogenesis, metabolic changes essential for alternative activation, and the repair functions of M2 macrophages [63].

Figure 2.

The role of PPARγ in macrophage dynamics during wound healing. This schematic illustrates the central role of PPARγ in macrophage polarization during wound healing. Pro‐inflammatory M1 macrophages secrete TNF‐α, IL‐6, and iNOS under IFNγ/LPS stimulation. PPARγ activation via the IL‐4/IL‐13/pSTAT6 axis drives metabolic reprogramming (fatty acid β‐oxidation) and M2 polarization, enhanced by HO‐1/CO, T166 dephosphorylation, and PAQR3‐STUB1‐mediated stabilization. M2 macrophages express Arg1/CD206 and secrete IL‐10/TGF‐β1, promoting tissue repair and angiogenesis. PPARγ agonists (rosiglitazone, lonicerin) balance M1/M2 polarization while inhibiting NF‐κB, accelerating inflammation resolution and wound healing. Inhibitors (arsenide, GW9662) block this transition.

Regulatory networks: Several pathways converge on PPARγ to regulate M2 polarization. The HO‐1/carbon monoxide (CO) axis upregulates PPARγ to promote M2 polarization [64]. The E2F1 transcription factor acts as a negative regulator of PPARγ; E2F1 deficiency enhances PPARγ expression and accelerates wound healing via M2 macrophages [65]. The PAQR3‐STUB1 axis controls PPARγ protein stability via ubiquitination; knocking down PAQR3 stabilizes PPARγ, enhances M2 polarization, and improves diabetic wound healing [66]. PPARγ T166 dephosphorylation in macrophages triggers a lipid synthesis program that supports the secretion of reparative factors, a process critical for tissue repair [67].

4.2. Effects of PPARγ on Keratinocytes

PPARγ is expressed in keratinocytes and its activation is crucial for multiple aspects of re‐epithelialization (Figure 3).

Figure 3.

Spatiotemporal regulation of wound healing by PPARγ in keratinocytes. PPARγ orchestrates keratinocyte functions during wound repair: (1) Decreases on Day 1 post‐injury; (2) promotes migration via cytoskeletal reorganization; (3) enhances proliferation (Cyclin D1/FOSL1) but PCNA increases in PPARγ KO; (4) induces differentiation markers (filaggrin/loricrin) via AP‐1/p38; (5) upregulates AQP3 and glycerol uptake; (6) mediates oxidative stress responses. Aging reduces PGC‐1α, impairing proliferation and delaying healing. Arrows indicate activation pathways.

Promotion of differentiation: PPARγ agonists upregulate the expression of differentiation markers (e.g., filaggrin, loricrin) in human keratinocytes, reinforcing the epidermal barrier [6, 42].

Enhancement of hydration: PPARγ activators stimulate aquaporin‐3 (AQP3) expression and glycerol uptake in keratinocytes, contributing to skin hydration [68].

Dynamic expression in healing: PPARγ expression in keratinocytes decreases initially after wounding but rises significantly in the later stages of repair, suggesting a primary role in the proliferative and remodeling phases [47].

Metabolic support: The PPARγ‐PGC‐1α axis maintains NAD+ homeostasis and mitochondrial function in keratinocytes, which is critical for their proliferation and migration during aging and wound repair [69].

4.3. PPARγ Regulates Adipocyte Differentiation to Accelerate Wound Healing

Dermal adipocytes play an active role in wound repair, and PPARγ is the master regulator of adipocyte differentiation (Figure 4).

Figure 4.

PPARγ‐mediated adipocyte differentiation accelerates wound healing through multi‐pathway regulation. PPARγ activation promotes nuclear translocation to induce FGF1 expression via PPRE binding, drives pre‐adipocyte differentiation with upregulated C/EBPα/adiponectin, and suppresses TNF‐α inflammation/apoptosis. BMP‐4 enhances adipogenesis through CITED2‐SMAD‐C/EBPβ signaling. MAPK pathways exhibit context‐dependent regulation of differentiation, while NF‐κB modulates CXCL2 expression inhibited by rosiglitazone. PPARγ‐modRNA specifically accelerates diabetic wound healing. Fatty acid release via ATGL activates GPR84 signaling in wound microenvironment. T166 dephosphorylation regulates metabolic balance independently.

Induction of adipogenesis: PPARγ activation drives the differentiation of preadipocytes into mature adipocytes, upregulating genes like C/EBPα and adiponectin [7, 25]. Chemically modified PPARγ mRNA (PPARγ‐modRNA) has been shown to accelerate wound healing by enhancing adipogenesis [7].

Modulation of the wound microenvironment: Upon skin injury, adipocytes increase lipolysis via adipose triglyceride lipase (ATGL), releasing fatty acids that can activate macrophages and other cells via G‐protein‐coupled receptors (e.g., GPR84), thereby influencing the wound milieu [70, 71].

Cross‐talk with other pathways: Adipogenic signals like BMP‐4 can enhance PPARγ‐mediated differentiation through SMAD signaling and the coactivator CITED2 [10].

4.4. The Role of PPARγ‐Regulated Angiogenesis in Wound Healing

PPARγ exerts context‐dependent effects on angiogenesis, generally promoting physiological repair while potentially inhibiting pathological vessel growth.

Pro‐angiogenic effects: PPARγ activation can enhance angiogenesis by upregulating VEGF expression in vascular smooth muscle cells and macrophages [72], and by improving the function of endothelial progenitor cells (EPCs) [73]. In diabetic models, PPARγ agonists can partially restore impaired angiogenesis [74].

Dual regulation and specificity: The pro‐angiogenic effect of factors like FGF21 on brain microvascular endothelial cells requires PPARγ activation [75]. Conversely, in specific contexts like the porcine placenta, PPARγ can either stimulate or inhibit angiogenesis depending on the VEGF isoforms involved [76]. In corneal injury, PPARγ activation can reduce pathological neovascularization [77].

4.5. PPARγ Affects Wound Healing by Regulating Metabolism and Mitochondrial Function

Cellular metabolism and mitochondrial dynamics are reprogrammed during wound healing, and PPARγ is a key modulator of this process.

Enhancement of mitochondrial function: PPARγ agonists enhance mitochondrial biogenesis, oxidative phosphorylation efficiency, and antioxidant capacity, often through upregulating PGC‐1α [63, 69, 78].

Metabolic support for repair: In keratinocytes, the PPARγ‐PGC‐1α axis maintains NAD+ levels and promotes fatty acid oxidation, providing energy and biosynthetic precursors crucial for re‐epithelialization. Age‐related decline in this axis contributes to healing deficiencies [69].

Anti‐inflammatory metabolic shift: In macrophages, PPARγ‐driven fatty acid oxidation supports the anti‐inflammatory, pro‐repair M2 phenotype [63].

5. PPARγ Affects Wound Healing by Regulating Epithelial–Mesenchymal Transition

Epithelial–mesenchymal transition (EMT) is a process where epithelial cells acquire mesenchymal traits, contributing to wound re‐epithelialization and, if dysregulated, to fibrosis. PPARγ exerts a dual and context‐dependent role in regulating EMT.

Inhibition of profibrotic EMT: PPARγ and its agonists can inhibit TGF‐β‐induced EMT in various models, thereby reducing fibrosis and scar formation. This is achieved by interfering with SMAD signaling and other profibrotic pathways [9, 79, 80].

Context‐dependent effects: While generally anti‐fibrotic, PPARγ can sometimes promote EMT in certain tumor microenvironments through mechanisms involving TGFβ1 upregulation or other pathways [81]. This highlights its nuanced role in tissue plasticity.

6. The Involvement of PPARγ in Modulating Wound Healing and Inhibiting Scar Formation Through the Regulation of Fibroblasts

During healing, fibroblasts differentiate into contractile myofibroblasts that drive wound contraction and ECM deposition. The persistence of myofibroblasts leads to excessive scarring (Figure 5). PPARγ acts as a potent endogenous antifibrotic factor.

Figure 5.

PPARγ regulates scar formation via fibroblast modulation. Upon vascular injury, TGF‐β1/PDGF activates fibroblast migration and myofibroblast differentiation (α‐SMA↑), driving ECM deposition. Intracellular PPARγ in fibroblasts: (1) Inhibits TGF‐β/Smad signaling by blocking p300; (2) activates IL‐10/PI3K/AKT/STAT3 pathway; (3) promotes adipocyte‐derived BMP‐4 secretion, inducing SMAD1/5/9/CEBPβ. This triad suppresses myofibroblast activation and ECM overproduction (Collagen III/fibronectin↓), maintaining healing‐fibrosis balance to prevent pathological scarring.

Suppression of myofibroblast activation: PPARγ activation in skin fibroblasts counteracts the profibrotic effects of TGF‐β1, reducing the expression of α‐smooth muscle actin (α‐SMA) and ECM components like collagen. This occurs through mechanisms such as disrupting the TGF‐β/Smad pathway and enhancing IL‐10 production [82, 83].

Paracrine regulation by adipocytes: Adipocyte‐derived factors, notably BMP‐4, can activate PPARγ in fibroblasts and promote myofibroblast dedifferentiation via the SMAD1/5/9 pathway and CITED2, offering a novel mechanism for scar inhibition [10].

Evidence in other tissues: PPARγ’s anti‐scarring properties are also evident in corneal healing, where it reduces corneal haze and fibrosis by inhibiting fibroblast migration and ECM synthesis [84, 85].

7. Clinical Application Prospects and Challenges of PPARγ

7.1. Promising Preclinical Strategies

Current research explores innovative approaches to harness PPARγ for wound repair. These include the use of chemically modified PPARγ mRNA (PPARγ‐modRNA) to directly and transiently boost PPARγ expression in adipocytes, enhancing tissue regeneration [7]. Another strategy focuses on developing biomaterials that leverage PPARγ’s role in macrophage polarization to shift the wound microenvironment from pro‐inflammatory to pro‐regenerative [86].

7.2. Challenges in Clinical Translation

The translation of PPARγ‐targeted therapies faces significant hurdles. The foremost is safety concerns associated with conventional TZD agonists (e.g., rosiglitazone, pioglitazone), which include weight gain, edema, cardiovascular risks, and bone loss, limiting their use for chronic conditions like wound healing [13, 87]. Furthermore, the mechanistic complexity of PPARγ’s actions within the multicellular wound environment necessitates a deeper understanding for precise targeting.

7.3. Current Clinical Evidence and Trials

Contrary to the notion of a complete absence of clinical data, several clinical investigations have explored PPARγ agonists in wound healing contexts. For instance, a study on pioglitazone in diabetic patients showed improved wound healing outcomes [88]. Preclinical studies further elucidate the mechanism, demonstrating that pioglitazone pretreatment enhances the therapeutic potential of stem cells in diabetic wound models. While these studies demonstrate proof‐of‐concept, they confirm the need for safer and more targeted PPARγ modulators.

7.4. Future Directions

Future efforts should focus on the following: (1) Developing precise delivery systems (e.g., nanoparticles, topical formulations) to achieve local activation and reduce systemic exposure; (2) designing novel, safer agonists with improved selectivity; (3) personalizing therapies based on wound etiology and patient genetics; and (4) exploring combination therapies that target PPARγ alongside other regenerative pathways.

8. Conclusion

In conclusion, PPARγ plays a crucial role in wound repair by orchestrating immune regulation, adipose tissue regeneration, and angiogenesis (Figure 6). Nevertheless, challenges such as the adverse effects of conventional agonists, unclear regulatory pathways in intricate microenvironments, and inadequate clinical evidence hinder its practical implementation. Future investigations should focus on creating sophisticated delivery systems through interdisciplinary partnerships and enhancing clinical verification alongside personalized medicine approaches. These efforts are essential for the successful transition of PPARγ‐targeted therapy from experimental settings to clinical practice, ultimately improving outcomes for patients with wounds.

Figure 6.

PPARγ orchestrates wound healing. This schematic depicts PPARγ’s central role across wound healing phases (Inflammatory, Proliferative, Remodeling). Upon ligand binding and RXR heterodimerization (with CBP/p300 coactivation), PPARγ: (1) Polarizes macrophages from pro‐inflammatory (M1; TNF‐α, IL‐1β) to pro‐regenerative (M2; IL‐10, TGF‐β), suppressing inflammation; (2) accelerates re‐epithelialization via keratinocyte migration (↑E‐cadherin/Rac1) and wound closure; (3) drives tissue regeneration (angiogenesis, adipogenesis); (4) minimizes scarring while guiding repair and enhances metabolic support (mitochondrial biogenesis, GLUT4 translocation). Despite promoting granulation tissue and collagen remodeling, clinical translation of PPARγ agonists faces challenges.

Nomenclature

AQP3

aquaporin 3

COX‐2

cyclooxygenase‐2

ECM

extracellular matrix

EMT

epithelial‐mesenchymal transition

EPCs

endothelial progenitor cells

HIF‐1α

hypoxia‐inducible factor 1‐alpha

IL

interleukin

KCs

keratinocytes

MMPs

matrix metalloproteinases

OXPHOS

oxidative phosphorylation

PCNA

proliferating cell nuclear antigen

PDGF

platelet‐derived growth factor

PGC

peroxisome proliferator‐activated receptor γ co‐activator

PPARγ

peroxisome proliferator‐activated receptor gamma

PPRE

PPAR response element

TGF‐β

transforming growth factor‐beta

TIMPs

tissue inhibitors of metalloproteinases

TNF‐α

tumor necrosis factor‐alpha

TZDs

thiazolidinediones

VEGF

vascular endothelial growth factor

Ethics Statement

The authors have nothing to report.

Consent

All authors agree to publish this review.

Disclosure

All authors have read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

Jianan Wang, Zhaojun Wang, and Kaixing Jia contributed equally to this work and were mainly responsible for literature review and drafting the manuscript. Xiaolong Du, Yueyan Wu, Wei Wang, and Jianan Wang guided the research strategy, critically reviewed the intellectual content of the manuscript. All contributors are listed as authors; no unacknowledged individuals or third‐party services were involved.

Funding

This study was supported by Lvliang City Key Research and Development Project (Social Development No. 2020SHFZ39); the Fenyang Hospital’s Scientific Research Program, No. 2024013 and No. 2024021.

Wang, Zhaojun , Jia, Kaixing , Wang, Wei , Du, Xiaolong , Wu, Yueyan , Wang, Jianan , The Mechanistic Role of PPARγ in Wound Healing, PPAR Research, 2026, 2242856, 13 pages, 2026. 10.1155/ppar/2242856

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.