Peptides in Regenerative Medicine: Mechanisms, Evidence, and Translational Status

1.0. Introduction:

Regenerative medicine is a growing field that seeks to restores tissue structure and function after an injury, degeneration to tissue, or when metabolic stress occurs, and depends on signals that can direct cell survival, proliferation, differentiation, and immune regulation [1,2,3]. Peptides are well suited for the goal of regenerative medicine because they act as endogenous signaling molecules and can engage in defined receptors and pathways that govern biology, rather than functioning as nonspecific stimulants [1,2,3]. Peptides occupy a useful ground between small molecules and large biologics. Their size and sequence defined structure allow them to have a high target selectivity and potency, while accessibility and lower complexity, relative to larger protein therapeutics, make them an attractive tool for translational development [1,3,4,5].

Peptides are typically synthesized using solid-phase peptide synthesis, where amino acids are sequentially coupled to a growing chain which is anchored to a resin, followed by cleavage and deprotection to release the finished peptide [6,7]. The versatility and accessibility of peptide synthesis have contributed to rapid expansion of peptide-based therapeutics, with more than 80 peptide drugs reaching the market. The field has moved well beyond just being replacement hormones, and now include engineered analogs, receptor agonists, and bioactive peptides used across metabolic, inflammatory, cardiovascular, antimicrobial, and pain indications [1,4,5].

A central reason that peptides are important in the field of regenerative medicine is their mechanistic fit. Many regenerative processes are governed by ligand-receptor systems, and downstream kinase networks, which include MAPK, PI3K-AKT, STAT, and AMPK, all of which can be modulated by peptide signals that shape proliferation, survival, metabolism, and tissue remodeling [2,8].

When incorporated into scaffolds, coatings, or delivery systems, peptide motifs can impart angiogenic, neurotrophic, and anti-apoptotic functions, which allow these biomaterials to actively instruct tissue repair, rather than simply providing structural support [3]. For example, mitochondrial peptide signaling provides an improved insulin sensitivity and metabolic homeostasis through effects linked to skeletal muscle and AMPK activation, again highlighting importance of metabolic control in tissue maintenance and recovery [8]. Tesamorelin further supports the idea that peptide therapy can remodel tissue-level phenotypes in humans. It reduces visceral adipose tissue in treated patients without major disruption of glucose parameters, showing that peptide signaling can produce sustained changes in body composition related to tissue health and repair capacity [9]. Additionally, this expanding therapeutic footprint reflects a broader translational shift in peptide drug discovery, in which chemical modification and improved design strategies enhance peptide stability and expand the potential for peptide-based therapies in regenerative medicine applications [10].

It should be noted that peptide translation is not straightforward, and there are limitations as short plasma half-life, proteolytic degradation, and delivery barriers all have limited use of peptides, which is why modern peptide development relies on sequence engineering, cyclization, conjugation and delivery strategies all done to improve stability, and tissue access [4,5,11]. This review, therefore, examines peptides that represent distinct mechanistic routes in regenerative medicine. By evaluating peptides actions, experimental and clinical evidence, and current translational status, this review aims to define where peptide therapeutics are used as regenerative tools and where the evidence may remain preliminary.

2.0. Methodology:

This literature search was conducted using a structured search of the PubMed database to identify studies evaluating the role of peptides in regenerative medicine, with emphasis on mechanisms of action, preclinical evidence, and clinical or translational relevance. Articles were identified using relevant keywords and Boolean combinations, including “peptide”, “peptide therapeutics”, “regenerative medicine”, “tissue repair”, “wound healing”, FGF-18”, and “tesmaroelin”. Additional targeted searches were conducted for individual peptides and regenerative applications such as repair and healing. Additional articles were identified through manual screening of reference lists from the relevant publications. No strict date restrictions were applied to this search, and studies were selected based on their relevance to peptide-mediated tissue repair, regeneration, and their translational potential. Eligible publications included preclinical studies, clinical studies, and narrative reviews among others. Priority was given to peer reviewed studies and higher-level forms of evidence when available.

3.0. Peptide Reviews:

Although these peptides act through distinct molecular pathways, they converge on several shared biological processes that promote tissue repair and regeneration (Table 1).

3.1. Fibroblast Growth Factor—18 (FGF-18)

History and Development

Fibroblast growth factor-18 (FGF-18) is a member of the FGF family that was identified as a regulator of skeletal development and cartilage homeostasis. Its role in controlling chondrocyte activity and matrix formulation made it a therapeutic target for cartilage regeneration, particularly in osteoarthritis where progressive cartilage loss has few disease-modifying treatment options [12,13]. The regenerative potential of FGF-18 led to the development of sprifermin, a recombinant human FGF-18 designed for intra-articular administration. Unlike therapies that are primarily aimed at symptomatic relief, sprifermin was developed to preserve and to restore articular cartilage by stimulating anabolic activity within resident chondrocytes [13,14].

Structure and Mechanism of Action

FGF-18 mediates biological effects primarily through effects with FGF receptor-3 (FGFR3). Activation of its signaling pathway regulates chondrocyte proliferation, differentiation, and extracellular matrix production, which all are essential in the maintenance of cartilage structure while supporting tissue repair [12]. Experimental studies have demonstrated that FGF-18 signaling promotes synthesis of cartilage-specific extracellular matrix components, including type II collagen and proteoglycans, while facilitating chondrocyte maturation [12]. Loss of FGFR3 signaling impairs cartilage nodule formation and matrix production, which highlights this receptors receptor-ligand interaction during cartilage regeneration and importance during this process [12]. Additionally, experimental studies have demonstrated that FGF-18 stimulates proliferation of mature articular chondrocytes while enhancing extracellular matrix production both in vivo and in vitro. Expression of FGF-18 together with FGFR2 and FGFR3 in normal human articular cartilage suggests that this signaling pathway contributes to the maintenance of cartilage under physiologic conditions [15].

Clinical Data

In animal studies of cartilage injury, intra-articular sprifermin enhanced cartilage repair, increases expression of cartilage matrix genes, and improves histological outcomes, while producing more structural healing following microfracture compared to control treatment of saline [13,16]. Human clinical trials have demonstrated that sprifermin preserves cartilage structure in patients with knee osteoarthritis as well. Randomized studies have reported that dose-dependent reduction in cartilage loss were seen with a favorable safety profile, which provides supporting evidence of successful translation from experimental models to clinical investigation [13,14]. Comparison of animal and human studies demonstrate consistent biological activity across both settings. Animal models show cartilage regeneration with clear structural and functional improvements, and human trials have demonstrated preservation of cartilage morphology with less consistent effects on pain and clinical symptoms [13,14,16]. These findings support continued investigation of FGF-18 as a disease-modifying therapy for cartilage repair. Notably, an unbiased post-hoc-re-analyses of the FORWARD trial found that the structural gains in cartilage thickness achieved during active treatment were maintained for at least three years after the sprifermin discontinuation, which suggests that there is a durable regenerative effect, rather than just a transient pharmacologic response with peptides in regenerative medicine therapy [17].

3.2. Thymosin Beta-4 (TB4)

History and Development

Thymosin beta-4 (TB4) was isolated originally from the thymus as a member of the thymosin family and was later recognized as the predominant beta thymosin peptide in mammalian tissues [18,19]. Further studies demonstrated that TB4 is widely distributed throughout multiple organs and released following tissue injury, which led to investigation of the role it has as an endogenous mediator of tissue repair. Interest in TB4 as a regenerative therapeutic developed from observations that biological functions extend beyond immune regulation. Experimental studies have identified roles in wound healing, angiogenesis, cell migration, and tissue remodeling, which prompted evaluation in cardiovascular, and musculoskeletal models of injury [18,19].

Structure and Mechanism of Action

TB4 is a natural occurring peptide composed of 43 amino acids, and is the major G-actin-binding peptide that is in mammalian cells [18,19,20]. The binding of monomeric actin allows TB4 to regulate cytoskeletal organization, cell migration, and cellular responses required for tissue repair. The regenerative effects of TB4 result from several complementary biological actions. TB4 promotes endothelial cell migration, angiogenesis, and extracellular matrix remodeling, while also suppressing apoptosis and inflammatory signaling [18,19,21]. These coordinated effects all create an environment that supports tissue repair rather than targeting a single signaling pathway. Mechanistic studies have further demonstrated that the actin-binding region of TB4 is required for its angiogenic activity. Short peptide fragments containing the motif all retain the ability to stimulate endothelial migration, and vessel angiogenesis, whereas fragments that were studied that contained a lack of actin-binding sequence lost biologic activity, which identifies and supports this actin binding region as being a critical part of TB4 and its function [18,19,21].

Clinical Data

Preclinical studies have consistently demonstrated regenerative effects across multiple tissues. In experimental wound models, TB4 accelerates re-epithelization, enhances collagen deposition, promotes angiogenesis, stimulates keratinocyte migration, and also improves wound contraction compared with untreated controls [22]. Beyond just cutaneous repair, animal studies have reported beneficial effects in myocardial infarction, ischemia-reperfusion injury, and central nervous system injury.

These findings have suggested that TB4 acts through conserved repair mechanisms that are applicable across multiple organ systems [18,19]. Comparison of animal and human evidence has also demonstrated that biological actions of TB4 are well established in experimental models, whereas clinical translation has remained more limited. Early clinical studies have also evaluated TB4 in conditions that include dermal wounds with favorable safety; however, most evidence supports regenerative potential continues to originate from preclinical investigations, and well-designed clinical trials are needed for definite conclusions regarding efficacy across tissue-specific conditions [18,21]. In this regard, one of the developed human datasets comes from the ocular application, where a randomized placebo-controlled phase 2 clinical trial of topical TB4 significantly improved severe dry eye disease, which offers a direct clinical support and evidence for TB4 and its regenerative as well as anti-inflammatory action at the tissue level [23].

3.3. GHK-Cu

History and Development

GHK (glycyl-L-histidyl-L-lysine) was first isolated from human plasma in 1973 after investigators observed that it restored protein synthesis in aged human liver tissue to a younger profile, which established GHK as a endogenous peptide involved in tissue repair and maintenance [24]. Subsequent work has demonstrated that GHK binds to copper (Cu²⁺) with very high affinity to form GHK-Cu, which is a biologically active complex that is responsible for regenerative effects, and because free copper is readily available in physiologic conditions, it is believed that GHK exists predominantly as GHK-Cu in vivo [24,25,26]. Over many decades, GHK-Cu became a widely studied peptide in skin repair, connective tissue remodeling, and wound healing, which lead to incorporation into topical dermatologic and cosmetic formulations because of favorable safety profile [25,27,28]. More recent studies have expanded interest toward broader regenerative applications looking at effects on gene regulation and tissue homeostasis.

Structure and Mechanism of Action

GHK is a naturally occurring tripeptide composed of glycine, histidine, and lysine, and the histidine and terminal amino group both work together to coordinate the Cu²⁺ to form a stable GHK-Cu complex that facilitates copper delivery, while minimizing copper-mediated oxidative toxicity [24]. GHK-Cu promoters extracellular matrix remodeling by stimulating dermal fibroblasts and increases synthesis of collagen, elastin, glycosaminoglycans, and decorin, while regulating matrix metalloproteinases and inhibitors [25,27,28]. It also supports angiogenesis, nerve outgrowth, and suppresses inflammatory signaling pathways, including NF-KB, which creates a favorable environment used for tissue repair. Additionally, rapid degradation of native GHK-Cu promoted development of peptide based delivery systems, where incorporation into self-assembling nanostructures improved peptide stability and enhances wound healing activity by sustaining biologic effects [29].

Clinical Data

The regenerative effects of GHK-Cu are primarily supported by preclinical studies. Animals and in vitro models demonstrate accelerated wound healing, enhanced collagen organization, angiogenesis, and matrix remodeling [25,27,28]. Human trials remain limited, however, it has been used in topical dermatologic and wound-care products for many years, and a small pilot study in patients with inflammatory bowel disease reported improvements in clinical, endoscopic, and histologic outcomes following rectal GHK-Cu treatment [25,26,28]. Beyond just wound repair, GHK has also been shown to reduce senescence markers and restore a younger phenotype in aged fibroblasts, which supports the proposed role it has in resolving fibrotic tissue remodeling as part of a regenerative profile for GHK [30].

3.4. MOTS-c

History and Development

MOTS-c (mitochondrial open reading frame of the 12s rRNA-c) was identified in 2015 as a 16 amino acid peptide encoded by a short reading frame within mitochondrial 12s rRNA [8]. Unlike conventional peptide hormones encoded by the nuclear genome, MOTS-c is encoded by mitochondrial DNA and functions as a mitochondria-derived peptide (MDP) and this finding introduced a new mechanism of communication between the nucleus and the mitochondria [8,31,32]. Subsequent studies have expanded the biologic role of MOTS-c beyond metabolism, and demonstrated its impact on muscle structure and function, bone metabolism, immune regulation, aging and tissue repair, supporting potential in regenerative medicine. These observations led to interest in MOTS-c as a therapeutic candidate for metabolic and degenerative disorders [31,33].

Structure and Mechanism of Action

MOTS-c, a 16 amino acid peptide, is able to change its cellular distribution by moving from the mitochondria to the nucleus when cells experience periods of stress, where it then regulates nuclear gene expression involved in cellular adaption and survival [8,31]. Its mechanism involves the disruption of the folate-methionine cycle, leading to the activation of the AICAR-AMPK signaling process, which leads to the stimulation of AMPK, improving glucose utilization, enhancing insulin sensitivity, and promote mitochondrial homeostasis [8,33,34]. MOTS-c also regulates pathways in tissue repair, including SIRT1 and IL-10 signaling, and collectively, these pathways in tissue repair reduce oxidative stress, limit apoptosis and support extracellular matrix synthesis in injured tissues [33,34,35,36]. Recent regenerative studies have demonstrated that sustained delivery of MOTS-c through a self-assembling peptide hydrogel preserved nucleus pulposus stem cell viability, which reduced cellular senescence, and slowed intervertebral disc degeneration through AMPK/SIRT1 signaling [35].

Clinical Data

In rodent models, exogenous MOTS-c prevented diet induced obesity, improved insulin sensitivity, preserved skeletal muscle mitochondria function, and protected against age-related metabolic dysfunction [8,34]. In regenerative models MOTS-c also show promising results in animal studies, where MOTS-c improved survival of mesenchymal stem cells under oxidative stress and enhanced structural repair in a rat model of intervertebral disc degeneration [35]. MOTS-c regenerative influence also extends into the skeleton, where it has been shown to promote osteoblast proliferation and differentiation, while also suppressing osteoclast activity, which positions it as a candidate for being a peptide with bone tissue regeneration capabilities, in addition to its role as a metabolic and disc repair therapy [37].

3.5. Tesamorelin

History and Development

Tesamorelin became the first FDA-approved GHRH analogue for attenuating visceral abnormal fat distribution that is associated with HIV-associated lipodystrophy [38]. Tesamorelin is a synthetic analogue of human growth hormone-releasing hormone (GHRH1-44) that was engineered to improve peptide stability while preserving the biologic activity of native GHRH. By stimulating endogenous growth hormone secretion, rather than supplying exogenous growth hormone, tesamorelin produces an increased physiologic activation of the GH/IGF-1 axis [39,40]. Additionally, it was developed to stimulate growth hormone secretion while also resisting rapid enzymatic degradation.

Structure and Mechanism of Action

Tesamorelin binds to GHRH receptors of the anterior pituitary gland which stimulates pulsatile secretion of endogenous growth hormone. The subsequent rise of circulating IGF-1 activates anabolic pathways involved in protein synthesis, lipid metabolism, and tissue maintenance while preserving the normal endocrine feedback mechanism [39,40]. Activation of the GH/IGF-1 axis promotes selective lipolysis within visceral adipose tissue without producing a clinically meaningful loss of subcutaneous fat. This selective remodeling distinguishes tesamorelin from nonspecific weight loss therapies as well [9,39,40,41]. From a regenerative medicine perspective, tesamorelin acts through restoration of physiologic anabolic signaling rather than direct cellular regeneration. Its ability to improve tissue composition, reduce ectopic fat deposition, and support lean tissue maintenance provides a biologic basis for tissue remodeling and functional recovery [39,41,42].

Clinical Data

Clinical evidence on the use of tesamorelin is derived primarily by randomized controlled trials in humans, with limited preclinical animal data specifically evaluating tesamorelin. Across multiple studies, treatment reduces visceral adipose tissue while preserving the glucose homeostasis within a safe profile [9,39,40,41]. Human studies have also demonstrated benefits beyond visceral fat reduction, with tesamorelin improving lean body mass, skeletal muscle density, and hepatic steatosis, which suggest restoration and regeneration of tissue function occurring rather than just simple changes in body composition [38,42,43]. Tesamorelin’s regenerative effects are exemplified in the liver, where visceral fat reduction is associated with improvement in hepatic enzyme levels, reinforcing the concept that its remodeling produces functional, organ-level tissue benefits and not just cosmetic fat loss [44]. Its effects on muscle, adipose tissue, and liver biology illustrate how peptides can promote structural and functional recovery, supporting their broader role in regenerative medicine.

4. Comparative Discussion

Mechanistic Classification

Peptides support regeneration by means of unique molecular mechanisms, and not just through a single biologic pathway. For example, sprifermin directly stimulates cartilage repair by activating anabolic FGF18/FGFR3 signaling, whereas tesamorelin restores endogenous GH/IGF-1 signaling to improve tissue metabolic regulation and body composition parameters [2,13,14,39,45]. Peptides such as GHK primarily promote extracellular matrix remodeling, angiogenesis, collagen synthesis, and modulation of inflammation, creating conditions that favor tissue repair instead of just replacing damaged tissue directly [24]. Mitochondrial peptides for example represent a separate mechanistic class that regulates cellular metabolism and stress responses through AMPK signaling, highlighting the importance of metabolic homeostasis in tissue regeneration [8].

Clinical Evidence

Clinical evidence is slowly growing for peptides targeting musculoskeletal and metabolic disorders. An example of this is in sprifermin, which demonstrates structural preservation of articular cartilage, while tesamorelin improves visceral adiposity, lean tissue, and hepatic health through endocrine regulation [13,14,39]. Current human studies consistently demonstrate improvements in tissue structure, body composition, or organ function, supporting peptides as being disease-modifying therapies [13,14,39]. Clinical success remains peptide-specific, emphasizing that regenerative medicine outcomes depends on selecting biologic targets that directly influence tissue repair and homeostasis [2,13,14,39,45]. This convergence of mechanistically distinct peptides around a shared regenerative endpoint has led some clinicians to describe injectable peptides broadly as emerging as an adjunct to regenerative medicine, even while the clinical data remains limited [46].

Despite increasing public interest, many commercially marketed peptide therapies outpace the available scientific evidence. Numerous peptides are promoted for anti-aging, musculoskeletal recovery, and performance enhancement despite an absence of rigorous randomized clinical trials and data. Clinicians should therefore be aware of this when counseling patients.

Peptide Delivery Limitations

Rapid enzymatic degradation, short plasma half-life, and poor oral bioavailability remain the major limitations for peptide therapeutics, often requiring repeated injections or structural modification [4]. Targeted delivery systems can improve the peptides stability, tissue retention, and local drug concentration, while still reducing the systemic exposure, which makes delivery technology an important component of regenerative therapy development [47].

5.0. Future Directions and Current Challenges

Future peptide therapeutics should continue to move beyond symptom management and focus on restoring tissue structure and function by targeting the endogenous repair pathways, extracellular matrix remodeling, and stem cell signaling (Table 2) [21,48]. The regenerative potential of peptides will depend on improving tissue-specific delivery. Advances in nanoparticle carriers, biomaterial scaffolds, and sustained-release systems may also increase local peptide concentration while also reducing systemic exposure and dosing frequency [47,49]. Limited bioavailability, rapid enzymatic degradation, and short circulating half-lives all remain barriers to widespread clinical use. This highlights need for peptide engineering strategies that improve stability without compromising biologic activity [5,49].

Although many peptides demonstrate promising regenerative effects in preclinical models, relatively few have been validated in large, randomized clinical trials. Stronger clinical evidence is required before there is widespread adoption [50]. The regenerative microenvironment should also receive greater attention in future studies, as peptide therapies may achieve greater efficacy when combined with biomaterials, stem cells, or tissue-engineered constructs which could support the cells survival and tissue integration [48]. Next-generation peptide discovery is expanding as well and it includes metabolically active and mitochondrial-derived peptides, which all provide new opportunities to regulate tissue repair through cellular hemostasis, as well as stress response pathways [33]. Continuous progression in regenerative medicine is required to standardize manufacturing, regulatory oversight, and high quality clinical trials to establish a long term safety understanding, durability of response, and improve therapeutic indications for peptide-based therapies [11,50].

6.0. Conclusions

Peptides are a promising class of therapeutics in regenerative medicine because of their ability to precisely target and regulate endogenous pathways that are involved in tissue repair, cellular survival, and proliferation. Unlike the nonspecific regenerative stimulants, peptides act through defined molecular targets that allow for biologic control of processes such as extracellular matrix remodeling, angiogenesis, metabolism, and inflammation. FGF-18, for example, has shown the potential of peptides being able to directly promote tissue regeneration through its cartilage-specific anabolic signaling, supporting its role as a disease-modifying approach for osteoarthritis and demonstrating how peptides can be used in this role. TB4 and GHK-Cu are another example that can highlight ability of peptides to create regenerative microenvironments to enhance wound healing, vascularization, collagen synthesis, and tissue remodeling as well. Mitochondrial peptides, which include MOTS-c, expand the regenerative strategies of peptides by targeting cellular metabolism, stress responses, and mitochondrial function to improve the tissue repair process. Tesamorelin illustrates how peptide-based modulation of endogenous hormones can promote tissue remodeling and improve functionality through metabolic regulation.

Current evidence supports strong regenerative activity in preclinical models, while clinical translation remains peptide-specific and is limited by the availability of large, long-term randomized trials. Major challenges in peptide therapeutics for regenerative medicine include rapid degradation, short half-life, limited bioavailability and delivery barriers. This emphasizes the importance of advancing delivery systems with peptide engineering. Overall, peptides are a versatile and evolving platform for regenerative medicine, with potential to shift treatment strategies from managing tissue damage toward actively restoring tissue structure and function. Future progress will depend on the integration of peptides with other biomaterials, tissue engineering constructs, and even more targeted delivery platforms to enhance the tissue specificity of peptides, their durability, and the effectiveness of this evolving therapy.