Effects of rosuvastatin treatment and other statins on burn wound healing

Abstract

Burn injuries represent a significant global public health concern and can result in severe complications. The process of burn wound recovery is intricate, dynamic and involves a series of synchronized events, such as hemostasis, inflammation, proliferation, revascularization, and remodeling. Obstacles in the healing of burn wounds are widespread, both in community and hospital settings. The correlation between the delay in wound-healing of burn injuries with increased mortality rates has led numerous investigators to devise novel therapeutic approaches aimed at accelerating the recovery of burn wounds. Statins, recognized for their varied pleiotropic impacts, have been proposed to enhance wound healing. Insights drawn from studies involving both animals and humans show that statins can speed up wound recovery. Rosuvastatin is one of the most recently studied statins. It promotes wound healing due to its hydrophilic characteristics, in combination with high hepatoselectivity and long half-life, which enable targeted action on the endothelium, improving microcirculation and promoting angiogenesis. Despite the encouraging preliminary results, it has not been widely used, resulting in limited data and heterogeneity. However, further high-quality, evidence-based research is urgently needed to identify whether rosuvastatin may present clinical advantages and improve burn wound recovery through angiogenesis, lymph-angiogenesis and microvascular function. Thus, rosuvastatin could be a potential alternative therapeutic approach for treating burn wounds.

Key Words: Rosuvastatin; Skin burns; Wound healing; Statins; Burn management

Core Tip: Burn injuries represent a significant global public health concern and can result in severe complications. The correlation between delays in the wound-healing process of burn injuries with increased mortality rates has led numerous investigators to devise novel therapeutic approaches aimed at accelerating the recovery of burn wounds. Statins, in addition to lowering cholesterol, enhance wound healing, particularly in burn wounds. The statins used include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and, more recently, Rosuvastatin, a synthetic hydrophilic statin with beneficial efficacy in burns.

INTRODUCTION

Burn injuries continue to pose a substantial public health burden, affecting an estimated 11 million individuals globally each year and resulting in approximately 180000 deaths annually, according to World Health Organization data[1]. The burden is especially severe in low-income and middle-income countries, where inadequate healthcare infrastructure contributes to poor outcomes. Even in high-resource settings, the economic and clinical challenges posed by severe burns–such as long hospital stays, the need for surgical intervention, and the risk of infections–remain formidable[2]. In addition to survival, the quality and speed of wound healing are crucial in minimizing long-term complications, such as hypertrophic scarring, contractures, and psychosocial impairment[3].

The wound healing process, particularly in burn wounds, is a dynamic and multi-phase biological sequence that includes hemostasis, inflammation, proliferation, extracellular matrix deposition, angiogenesis, and remodeling[4]. Effective healing depends on the timely transition through each of these phases. However, burn injuries often lead to excessive and prolonged inflammation, ischemia, and impaired vascularization–factors that critically delay wound closure and promote fibrosis[5]. Chronic wounds and delayed epithelialization increase susceptibility to infection, sepsis, and mortality.

While conventional treatments such as debridement, grafting, and advanced dressings improve outcomes, a significant portion of patients still develop complications that suggest a need for adjunctive therapies[6,7]. In this context, statins–a class of drugs developed to treat hypercholesterolemia–have garnered increasing attention for their potential in wound modulation due to their pleiotropic effects, which extend beyond lipid-lowering.

Statins primarily act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key rate-limiting enzyme in the cholesterol biosynthetic pathway[8]. Beyond lipid-lowering, they display a wide range of pleiotropic effects, including anti-inflammatory, antioxidant, anti-apoptotic, and endothelial-protective actions[9,10]. Within the context of wound repair, statins influence cytokine production such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), enhance endothelial nitric oxide synthase (eNOS) activity, and stimulate angiogenesis through upregulation of vascular endothelial growth factor (VEGF)[11]. These functions contribute to improved perfusion and optimized cellular responses within the wound microenvironment[12,13].

Among statins, rosuvastatin–a hydrophilic compound with high hepatoselectivity–is a promising agent for tissue regeneration. Unlike lipophilic statins [e.g., simvastatin (SMV), atorvastatin], rosuvastatin has reduced passive permeability across membranes but may exert its effects through endothelium-targeted actions[14]. Its high bioactivity and long half-life allow for more sustained modulation of endothelial and inflammatory responses[15]. Recent studies suggest that rosuvastatin may inhibit endothelial apoptosis and enhance VEGF-mediated neovascularization, which is critical for wound granulation and remodeling[16,17].

Animal models provide strong preclinical evidence for the benefits of rosuvastatin on wound healing. For example, Santana et al[1] reported enhanced type I and type III collagen deposition and improved epithelial regeneration in rabbit wounds treated with rosuvastatin gel, particularly when used in combination with platelet-rich plasma. Similarly, Marneri et al[2] reported that rosuvastatin significantly decreased TNF-α expression and accelerated wound closure in a partial-thickness burn model in rats. Additional research in orthopedic and dental models has demonstrated the ability of rosuvastatin to improve bone–tissue interface healing and osseointegration[18-20].

Given the limitations of systemic statin therapy–such as the risk of myopathy and hepatotoxicity–recent focus has shifted to topical delivery systems that localize the therapeutic effect at the wound site. A wide range of delivery vehicles (Vehs) have been developed, including transethosomal gels[21], cubosomal nanoparticles[22], nano sponges[13], and film-forming sprays[23], all of which aim to enhance percutaneous absorption, provide sustained drug release, and reduce systemic side effects. Salem et al[6] designed silver-capped hydrogel containing rosuvastatin-loaded nano cubes that significantly improved tissue granulation and angiogenesis in vivo.

Other systems integrate rosuvastatin into biological scaffolds, such as chitosan-based matrices and peptide-loaded hydrogels, which act as reservoirs for controlled release and provide structural support to regenerating tissue[18,24,25]. Some researchers have also combined rosuvastatin with mesenchymal stem cells (MSCs) to enhance their paracrine function and regenerative capacity, as demonstrated by Yu et al[26] and Rezvanian et al[27]. The applied healing topical statin delivery systems are shown in Table 1[6,13,18,21-25,27].

Table 1 Applied healing topical statin delivery systems.

Ref.	System
Salem et al[6], 2022	Silver-capped hydrogel
Aboelazayem et al[13], 2025	Nano sponges
Abu El Hawa et al[21], 2022	Transethosomal gels
Jull et al[22], 2022	Cubosomal nanoparticles
Patel et al[23], 2024	Film-forming sprays
Janipour et al[18], 2023; Heydari et al[24], 2022; Rahamathulla et al[25], 2024	Biological scaffolds (chitosan-based matrices and peptide-loaded hydrogels)
Yu et al[26], 2020; Rezvanian et al[27], 2021	Rosuvastatin with mesenchymal stem cells

In parallel, investigations with other statins reinforce the therapeutic rationale. SMV has been coloaded with adenosine or curcumin for enhanced wound closure[17,24], whereas atorvastatin has been embedded in electrospun membranes to stimulate MSC activity[20]. Furthermore, clinical studies suggest that statins may reduce hypertrophic scarring[28], prevent postsurgical fibrosis[12], and improve venous leg ulcer healing[22].

Despite its preclinical promise, human data on the use of rosuvastatin in wound healing remain limited. While some observational studies and case series on diabetic foot ulcers and surgical wounds have suggested benefits[21,29], randomized controlled trials are still lacking. Key knowledge gaps include the optimal dose, duration, and route of administration. Moreover, long-term safety, particularly with novel delivery systems, must be rigorously assessed.

From a translational standpoint, rosuvastatin’s multimodal actions on inflammation, angiogenesis, ECM remodeling, and endothelial protection make it a versatile agent for wound modulation. Its combination with emerging drug delivery technologies and regenerative therapies offers a novel paradigm for wound care, particularly in burn injuries, where conventional therapies often fall short.

In this narrative review, we evaluate the beneficial effects of rosuvastatin and other statins in relation to their role in wound healing, particularly in burn recovery. In this study, we thoroughly search the literature from PubMed until June 2025, focusing particularly on full-text studies published in English, mainly over the past ten years but also earlier in some cases.

SKIN ANATOMY AND FUNCTIONS

The skin is the largest organ of the human body, occupying an area of about 1.5-2.0 m² and weighing roughly 4.5–5.0 kg. It forms a continuous covering of the body’s external surface, with transitions to mucosal surfaces at several anatomical sites. Specifically, the skin merges with the conjunctival epithelium at the anterior eye, with the mucosa of the external auditory canal, and with the respiratory mucosa at the lips. It also continues into the gastrointestinal tract at the perineum and the urinary mucosa[30-32]. Its physiological functions include serving as a protective barrier, contributing to immune defense and thermoregulation, enabling sensory perception, and maintaining fluid and electrolyte homeostasis[33]. A schematic overview of skin functions is presented in Figure 1.

Figure 1 Scheme of skin functions.

From an embryological perspective, the skin originates from both the ectodermal and mesodermal germ layers. Structurally, it is composed of three principal components: (1) The epidermis; (2) The dermis; and (3) The subcutaneous tissue lying beneath. Serving as the interface with the external environment, the skin provides protection and maintains homeostasis. The epidermis consists of a stratified squamous epithelium organized into five distinct strata: From the surface inward, these are the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and basal layer. The dermis is subdivided into the superficial papillary layer and the deeper reticular layer. The papillary dermis is composed of loose connective tissue with relatively fewer collagen and elastin fibers, whereas the reticular dermis is denser, rich in collagen bundles and elastic fibers, conferring mechanical strength. Within the dermal matrix lie blood capillaries, nerve endings, and an extensive lymphatic network. The dermis also houses essential skin appendages, including hair follicles and exocrine glands, which open onto the surface[30,31].

The subcutaneous tissue consists of loose connective tissue and can be divided into three main components: (1) The external layer of subcutaneous fat; (2) The intermediate subcutaneous fascia; and (3) The innermost connective tissue. This compartment includes adipose tissue, vascular and lymphatic channels, as well as neural endings, playing a central role in thermoregulation and in anchoring the skin to the underlying structures[30,31].

Cutaneous perfusion is maintained by two vascular networks. The first is supplied by arteries that continue from the perforating vessels, traversing the superficial muscular fascia to reach the skin. Additionally, arteriovenous branches, also arising from perforator arteries, penetrate vertically into the subcutaneous tissue, where they merge to establish the subcutaneous vascular plexus[32,33].

The skin is also characterized by a highly specialized innervation. Within the basal and spinous layers of the epidermis, Merkel cells connected to Merkel discs mediate tactile responses. In the papillary dermis, Meissner corpuscles provide sensitivity to light touch, whereas Pacinian corpuscles, located deeper in the reticular dermis, detect vibration and pressure. Together, these neural elements coordinate the perception of pain, touch, temperature, and proprioceptive sensations[32,33].

Skin burns pathophysiology

Burns result from local tissue damage caused by direct exposure to heat on the skin. They are categorized by their cause: (1) Thermal; (2) Chemical; (3) Electrical; and (4) Radiation. Additionally, burns are classified into four categories based on depth: (1) First-degree burns affect only the skin, appearing red, swollen, and painful; (2) Second-degree burns extend into the dermis, showing marked redness and fluid-filled blisters; (3) Third-degree burns penetrate the entire skin thickness, characterized by vessel thrombosis, skin thickening, coagulative necrosis, and a burned grid. These injuries are painless due to nerve ending destruction; and (4) Fourth-degree burns extend beyond the skin, affecting underlying tissues[34,35].

Although burns trigger a more significant systemic inflammatory response than other wounds, their healing process follows the traditional wound healing model with three phases: (1) Inflammation; (2) Proliferation; and (3) Maturation[36-38].

The inflammatory phase begins immediately post-injury and is characterized by edema and redness. It consists of hemostasis, vasoconstriction and thrombus formation, and inflammation with vasodilation and phagocytosis. Macrophages release growth factors and cytokines to aid healing[39].

The second phase involves epithelium formation, capillary growth, granulomatous connective tissue development, and wound shrinkage. The third phase, known as the remodeling phase, includes the degradation of granular tissue, gradual replacement of collagen, and scar formation[40-42].

The speed and aesthetic recovery of burn healing correlate with burn depth. Superficial partial burns, involving skin necrosis with retained chorionic elements, heal within 5-7 days, leaving a small, high-quality, and elastic scar. In deep partial burns, where re-epithelialization takes longer, scars may be longer or hypertrophic[43-45].

STATINS: MECHANISM OF ACTION

The main pharmacological action of statins is the inhibition of HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG-CoA to mevalonate. By binding to the active site of HMG-CoA reductase, statins competitively block this enzymatic process, thereby suppressing endogenous cholesterol synthesis. As a result, hepatic cholesterol levels decline, leading to an upregulation of low-density lipoprotein (LDL) receptors on hepatocytes, which enhances the clearance of circulating LDL cholesterol and its lipoprotein derivatives[46].

Beyond their established lipid-lowering activity, statins have been suggested to exert a variety of so-called pleiotropic effects, many of which appear to be independent of their impact on cholesterol metabolism[47]. These additional properties include antithrombotic actions through improved endothelial function, stabilization of atherosclerotic plaques, reduction in thrombus development, antioxidant activity, immune system modulation, and effects on the central nervous system, glucose homeostasis, as well as bone and renal physiology[48,49]. Furthermore, a growing body of evidence highlights the prominent anti-inflammatory actions of statins.

One of the important anti-inflammatory mechanisms of statins involves the suppression of cellular adhesion molecules. These drugs lower the expression of monocyte CD11b, leukocyte lymphocyte function-associated antigen-1, CD40[50,51], and P-selectin in patients with acute coronary syndromes[52], thereby limiting the attachment of circulating inflammatory cells to the vascular endothelium and disrupting downstream inflammatory signaling. Beyond adhesion, statins also diminish the production of major proinflammatory mediators, including IL-6, IL-1β, TNF-α, IL-8, monocyte chemoattractant protein-1[53,54], and C-reactive protein (CRP). At the same time, they promote a shift toward anti-inflammatory responses by stimulating the release of type 2 helper T (Th2) cytokines[55] and decreasing macrophage and T-cell activity[56].

Although the cholesterol-lowering effect of statins is primarily mediated through the inhibition of mevalonate synthesis, a cholesterol precursor, their pleiotropic properties are largely attributed to the suppression of nonsteroidal isoprenoids such as farnesyl pyrophosphate (FPP) and ubiquinone. These molecules act as intermediates in the mevalonic acid pathway and play an essential role in protein isoprenylation. During this process, farnesyl and geranylgeranyl groups are covalently attached to specific proteins by dedicated transferases. Key substrates for this modification include the small GTP-binding proteins of the Rho, Ras, and Rac families, which anchor to cellular membranes and subsequently activate critical intracellular signaling cascades. By preventing protein isoprenylation, statins disrupt Rho-dependent signaling, thereby reducing the expression of adhesion molecules at endothelial sites of monocyte attachment, a pivotal step in vascular inflammation and atherogenesis[17].

One of the additional mechanisms through which statins exert their action is by attenuating nuclear factor-kappa B (NF-κB) activity in immune cells, which results in reduced transcription of adhesion molecules and inflammatory cytokines[57]. Beyond their vascular impact, these agents also modulate systemic inflammation, with one of the most consistent findings being the lowering of serum CRP concentrations[56].

The statins available for clinical use include older agents such as lovastatin, SMV, and pravastatin, as well as more recent synthetic compounds like fluvastatin, atorvastatin, and rosuvastatin (Figure 2). They can be classified either according to their source–naturally occurring statins such as lovastatin and its semi-synthetic analogues (SMV, pravastatin) vs fully synthetic molecules (fluvastatin, atorvastatin, rosuvastatin)–or by their physicochemical properties.

Figure 2 Scheme of currently available statins.

From the standpoint of solubility, atorvastatin, SMV, lovastatin, fluvastatin, and pitavastatin are considered lipophilic, enabling greater penetration across lipid membranes, whereas pravastatin and rosuvastatin are hydrophilic, displaying different pharmacokinetic characteristics[58,59]. A schematic overview of these diverse actions of statins is illustrated in Figure 3.

Figure 3 Scheme of statins effects. eNOS: Enhance endothelial nitric oxide synthase; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.

Rosuvastatin

Rosuvastatin is a fully synthetic, hydrophilic statin distinguished by its unique pharmacokinetic and pharmacodynamic characteristics. Among all statins, it possesses the longest elimination half-life, a property attributed to its structural capacity to bind simultaneously at multiple sites of the HMG-CoA reductase enzyme. This enhanced binding affinity enables effective inhibition of enzyme activity even at comparatively lower drug concentrations[60]. The hepatic selectivity of rosuvastatin contributes to reduced bioavailability in other tissues, minimizing myotoxicity post-administration. Furthermore, its metabolism primarily involves the 2C9 enzyme, with minimal engagement of 3A4 in cytochrome P450 (CYP450) pathways[61], explaining its minimal interactions with drugs that inhibit CYP450[61,62].

The hydrophilic nature of rosuvastatin, coupled with its hepatocyte selectivity, results in minimal passive diffusion through cell membranes and near-complete liver absorption[63,64]. Consequently, rosuvastatin outperforms SMV and pravastatin in its hypolipidemic effects[65,66] and wound healing. The hydrophilic characteristics of rosuvastatin, combined with its high hepatoselectivity and long half-life contribute to enhanced wound healing[1-3,5,6]. Rosuvastatin enables targeted action on the endothelium and microvasculature, reducing passive diffusion into non-hepatic tissues and minimizing potential adverse effects[1,5,6]. This action favors improved microcirculation and promotes angiogenesis, which are critical for wound healing. In addition, its pleiotropic effects include anti-inflammatory activity (inhibition of TNF-α, IL-6, and IL-1β), increased expression of VEGF and eNOS, antioxidant protection through inhibition of nicotinamide adenine dinucleotide phosphate oxidase (nicotinamide adenine nucleotide phosphate), and antiapoptotic effects on endothelial cells and fibroblasts[1-3,9,10]. This combination of properties creates a favorable microenvironment for rapid tissue regeneration[11,12].

Although rosuvastatin demonstrates a high degree of hepatoselectivity, there has been some concern regarding its biological effects in extrahepatic tissues where drug uptake is limited. Nevertheless, accumulating experimental data support the presence of pleiotropic actions. In particular, rosuvastatin interferes with the isoprenylation of small GTP-binding proteins belonging to the Rho and Ras families, which are critical regulators of intracellular signaling cascades. By reducing mevalonate production and thereby impairing isoprenoid synthesis, rosuvastatin ultimately prevents the activation of these signaling proteins and modulates downstream cellular responses[66].

Pleiotropic effects of rosuvastatin

A growing body of evidence indicates that rosuvastatin exerts pleiotropic actions, particularly through its anti-inflammatory properties, which may provide therapeutic benefit in a variety of neurological disorders including epilepsy, Alzheimer’s disease, Parkinson’s disease, spinal cord injury, and cerebral ischemia. For instance, Parson et al[67] demonstrated that rosuvastatin improves cutaneous microvascular function, an effect observed independently of alterations in LDL-cholesterol levels.

Similarly, Nangle et al[68] showed in streptozotocin-induced diabetic mice that rosuvastatin treatment enhanced vascular performance in both the corpus cavernosum and the aorta via mechanisms unrelated to lipid reduction.

Additional preclinical data reinforce these findings. Cameron et al[69] reported that rosuvastatin ameliorates deficits in sciatic motor and saphenous sensory nerve conduction, reduces thermal hyperalgesia, and improves blood flow in the superior cervical ganglion of diabetic mice, most likely through inhibition of the cholesterol biosynthetic pathway rather than direct lipid-lowering effects.

Likewise, Stalker et al[70] found that rosuvastatin downregulated endothelial adhesion molecules in rats, a process mediated by enhanced nitric oxide (NO) release from the endothelium. In agreement, Jungner et al[71] showed that rosuvastatin preserved cerebral microcirculation following traumatic brain injury, a benefit linked to increased NO production and reduced prostacyclin synthesis. Moreover, rosuvastatin pretreatment reduced oxidative stress and inflammation by inhibiting the upregulation of gp91 (phox) and p22 (phox) and decreasing NF-κB phosphorylation and inducible NO synthase (NOS) expression, thereby offering protection against cerebral ischemia[72].

Other studies have highlighted additional molecular targets. Grosser et al[73] identified heme oxygenase-1 as a potential mediator of the antioxidant and anti-inflammatory actions of rosuvastatin in endothelial cells, reinforcing the view that these effects are independent of cholesterol lowering. Furthermore, rosuvastatin has been reported to confer delayed neuroprotection against excitotoxic injury, a mechanism involving reduced calcium influx and subsequent suppression of superoxide anion generation, thereby promoting neuronal survival[74].

Pleiotropic effects of statins on wound healing

HMG-CoA reductase inhibitors are a family of drugs widely tested for the treatment of hypercholesterolemia, hyperlipidemia and atherosclerotic diseases. In addition to their basic role, statins present fewer known but widely recognized pleiotropic effects, such as antioxidative[75], anti-inflammatory[76], immunomodulatory[77] and angiogenetic effects. Prior studies have tested the applicability of statins for improving wound healing. SMV is one of the most well-studied statins for promoting wound healing. Wang et al[78] revealed that SMV may be an effective drug not only for prevention but also for the management of wounds infected by Staphylococcus aureus (S. aureus). When topically applied, SMV may exhibit antibacterial activity and reduce inflammation, bacterial loads and neutrophil infiltration. Moreover, another study claimed that SMV exerts antimicrobial activity against gram-positive organisms and especially against methicillin resistant S. aureus. Rosuvastatin impedes the production of critical methicillin-resistant S. aureus toxins on septic skin lesions. This process involves repressing various biosynthetic pathways and inhibiting protein synthesis in bacteria[79].

Other studies have shown that the topical application of SMV enhances angio-angiogenesis and lymph-angiogenesis during wound healing in diabetic mice. As many reports claim, lymph-angiogenesis is motivated by infiltrating macrophages, which are the main source of VEGF-C in cutaneous wound healing. Asai et al[80] reported that infiltrating macrophages were strongly increased and produced greater quantities of VEGF-C when SMV was topically used. Another study investigated the intraperitoneal use of SMV on the healing of 4 cm full-thickness longitudinal incisional wounds on diabetic mice. The data showed that diabetic mice treated with SMV had increased VEGF mRNA production on day 6 and elevated protein and NO expression. Additionally, SMV improved platelet endothelial cell adhesion molecule-1immunostaining on day 12 and promoted impaired wound healing in diabetic and normoglycemic mice[81]. Matsuno et al[82] demonstrated that the application of SMV controls endothelium regeneration through the upregulation of VEGF, leading to an improved endothelial healing process after vascular injury. Kureishi et al[83] investigated whether SMV can act protectively toward ischemic tissue. More precisely, SMV activates the protein kinase B (Akt) in endothelial cells and accelerates the phosphorylation of a peptide that contains the Akt phosphorylation site of eNOS. Thus, through Akt activation, statins may play a significant angiogenetic role in promoting new blood vessel growth and protecting endothelial cells from apoptosis. Mohajer Ansari et al[84] combined SMV and bone marrow mesenchymal stromal cells (BMSCs) to prove that this combination can enhance burn wound healing by positively influencing angiogenesis through the stromal-derived factor-1 alpha (SDF-1α)/chemokine receptor 4 (CXCR4) pathway. This study conducted deep partial-thickness burns on the interscapular region of 48 male rats under general anesthesia and used petroleum jelly, a single dose of intradermal BMSCs, topical SMV and a combination of BMSCs and SMV for 14 days. Based on their analyses, significant increases in the percentage of wound closure, epithelial thickness, and degree of collagen remodeling and the expression of SDF-1α, CXCR4, Akt, and phosphoinositide 3-kinase, as well as CD31 and VEGF, were noted in the SMV, BMSC, and combination treatment groups compared with the Veh group.

A separate study that used pravastatin demonstrated that impaired wound healing in diabetic mice may be related to abnormalities in NO and NOS availability. The authors investigated the effects of pravastatin on eNOS expression and the wound healing process in a diabetic wound-healing model. Laing et al[85] reported that the application of pravastatin sodium to dorsal incisions in diabetic Sprague-Dawley rats improved wound healing potential and hydroxyproline accumulation by increasing NOS and NO expression. Other evidence suggests that pravastatin reduces vessel dysfunction in radiation-induced skin lesions in mice. More precisely, Holler et al[86] demonstrated that pravastatin limits radiation-induced vascular activation, suppresses the production of inflammatory mediators and cytokines and increases endothelial NOS expression.

A recent investigation, supported by Akershoek et al[87], reported enhanced graft take in a porcine burn model when atorvastatin was administered. Reduced inflammation and enhanced vascularization were noted when atorvastatin was used. In addition to improving re-epithelialization, atorvastatin may facilitate the transition to the proliferative phase by accelerating the resolution of myofibroblasts.

Another small pilot study noted a potential positive impact of administering high-dose atorvastatin for six months on diabetic foot ulcers. Specifically, compared with low-dose atorvastatin, the 6-month administration of high-dose atorvastatin decreased the recurrence of new neuropathic diabetic foot ulcers[88].

Another recent study suggested a renovative strategy for preventing scars by administering functional wound dressings that may accelerate the wound process and reduce scar formation. Thus, Chen et al[89] suggested that incorporating lovastatin can enhance the inhibition of scar formation through a mechanism that is linked to nanofibers oriented perpendicular to the tension direction and that reregulates collagen organization during the initial phase of wound healing.

Furthermore, Yoshii et al[90] investigated the effects of local delivery of lovastatin on osteoblastic differentiation in vitro and new bone formation in vivo. According to the authors, 200 mg of lovastatin was sufficient to enhance new bone formation in a rat femoral plug model. The scaffold containing lovastatin continuously released the drug for 14 days. This extended release coincided with increased bone formation within segmental bone defects in the femurs of rats.

Pleiotropic effects of statins on burns

As mentioned above, burn injuries represent a significant global public health concern and can lead to severe complications. Numerous studies have highlighted the association between delayed wound healing and increased mortality rates. Consequently, researchers have explored novel therapeutic approaches to expedite the healing process of burn wounds.

A study conducted by Ramhormozi et al[91] demonstrated that the topical application of SMV may increase angiogenesis and collagen deposition and therefore may contribute to the amelioration of second-degree burn wounds. Additionally, through elevation of CD31, VEGF, a-smectic A, Akt and mammalian target of rapamycin levels, SMV facilitates wound closure.

In a separate study, investigators tested a self-nano emulsion delivery platform using coconut oil loaded with SMV. Experimental burn wounds were created on the dorsal skin using 1.5 cm heated biopsy punches. Treatment groups were assigned as follows: (1) The optimized nano emulsion with SMV; (2) The same formulation without SMV; (3) The formulation with oleic acid instead of coconut oil; (4) Aqueous SMV dispersion; and (5) Saline wash. The results underscored the significant synergistic impact of combining coconut oil and SMV for managing burn wounds. The mean burn wound diameter was reduced, IL-6 levels were decreased, and antimicrobial effects were intensified in the group where a blend of coconut oil and SMV was used[92].

Other experimental work has shown protective systemic effects of statins following burn injury. In murine models, SMV reduced hepatic apoptosis by blocking TNF-α and caspase-3 expression in hepatocytes, thereby mitigating burn-related liver injury[93].

Beffa et al[94] administered SMV or a placebo through intraperitoneal injection to mice that experienced a scald burn in the dorsal 30% total body surface area. The burn sepsis model exhibited a SMV-dependent improvement in survival. Their findings revealed improved survival in SMV-treated animals within the burn sepsis model, suggesting mortality reduction independent of IL-6 modulation.

In addition to SMV, atorvastatin was selected as the focal statin for investigation in another study. The choice was based on its notable lipophilic characteristics and its capacity to readily diffuse into tissues. This study focused on individuals who were administered atorvastatin during their hospitalization from 2016 to 2019 at the Roger W Seibel Burn Treatment Center (Buffalo, NY, United States). The outcomes revealed no adverse events or notable laboratory abnormalities linked to administering atorvastatin to treat patients with burns, and atorvastatin was effective at preventing the progression from partial to full-thickness wound injuries. Although a higher mortality rate than anticipated was observed in the patient group, the authors posit that this is likely attributable to the prehospital regimen of patients, which was associated with preexisting medical conditions[95].

An overview of the therapeutic efficacy of statins in burn wound healing is summarized in Table 2[84,87,91-95].

Table 2 Efficacy of statins on burn wound healing.

Ref.	Subjects	Model	Intervention	Groups	Effects
Ramhormozi et al[91], 2021	60 male Wistar rats	Wistar rats (2nd° burn)	Topical SMV in paraffin	SMV-Veh, RM, RM + SMV, RM-Veh	Activated protein kinase B/mammalian target of rapamycin signaling pathway
Mohajer Ansari et al[84], 2020	48 male Wistar rats	Wistar rats (deep partial burn)	Topical SMV ± BMSCs	Petroleum jelly, BMSCs, SMV	Improved wound closure, epithelial thickness, collagen remodeling
Hosny et al[92], 2020	57 + 15 adult rats (2 stages)	Adult rats	Topical SMV formulations	5-formulation: W/wo SMV, oleic acid, saline, dispersion	Reduced wound diameter, lower interleukin-6 with SMV-coconut oil
Boyko et al[95], 2020	48 burn patients	Burn patients	Oral atorvastatin	Atorvastatin, control	No adverse effects; safe in burns, effective
Akershoek et al[87], 2017	4 female pigs	Pigs (partial/full burn)	Oral atorvastatin/Losartan	No treatment, atorvastatin, losartan	Faster transition to proliferative phase; resolved myofibroblasts
Zhao et al[93], 2013	C57BL/6 male mice (approximately 70–90 total)	C57BL/6 mice (30% TBSA burn)	IP SMV ± inhibitors/KO	Sham, burn + saline, burn + SMV, tumor necrosis factor-α inhibitor/caspase-3, KO ± SMV	Reduced apoptosis via tumor necrosis factor-α/caspase-3 suppression
Beffa et al[94], 2011	48 male CD-1 mice	CD-1 mice (30% TBSA burn)	IP SMV	Placebo, SMV q12h, q24h	Improved survival at 24 hours and 72 hours (P < 0.01)

BMSCs: Bone marrow mesenchymal stromal cells; IP: Intraperitoneal; KO: Knockout; RM: Rapamycin; SMV: Simvastatin; TBSA: Total body surface area; Veh: Vehicle.

Pleiotropic effects of rosuvastatin on wound healing

Rosuvastatin calcium belongs to the class of statins, which effectively lowers circulating LDL cholesterol while simultaneously increasing high-density lipoprotein levels through inhibition of the enzyme HMG-CoA reductase. Experimental findings substantiate the significant role of this statin in wound healing[55,59,61,70,83].

Tanaka et al[96] demonstrated that rosuvastatin mitigates the impact of wound-healing inhibitors such as FPP, while enhancing endothelial cell activity and microvascular function, ultimately accelerating tissue repair.

Another study revealed that rosuvastatin treatment induces the expression of genes encoding proteins in osteoblasts, which leads to reduced local bone reabsorption and an amelioration of periodontal inflammatory conditions. According to a controlled clinical trial, administering rosuvastatin gel (1.2%) to patients with chronic periodontitis improved the repair process by suppressing associated inflammation[97].

Al-Kuraishy et al[98] reported that rosuvastatin has antimicrobial properties, either when administered alone or in conjunction with the antibiotic cefixime, against both gram-positive and gram-negative bacteria. This outcome was demonstrated by reduced minimum inhibitory concentration in the isolated cultures.

Similarly, Bao et al[99] reported that rosuvastatin exerts anti-inflammatory effects by suppressing proinflammatory cytokines, including IL-6 and TNF-α, thereby fostering a more favorable environment for wound regeneration.

Salem et al[6] attempted to encapsulate rosuvastatin-loaded nanocubic vesicles with silver nanoparticles (AgNPs) to increase rosuvastatin efficacy in wound management. These authors suggested that the topically applied hydrogel with AgNPs may effectively restore tissue integrity because of the synergistic effect of the two delivery systems on the wound healing process.

Other recently published studies aimed to develop and statistically optimize transethosomal formulations containing rosuvastatin to increase its effectiveness in facilitating topical wound healing. The efficacy of the formulation in promoting wound healing was assessed through an excision wound model and histological analysis. The findings revealed impressive wound healing effects, notably surpassing those of the standard 1% w/w silver sulfadiazine ointment. This favorable outcome is attributed to the penetration of transethosomes' nanosized vesicles into the skin, thereby augmenting the wound healing process[5].

Regrettably, rosuvastatin has various constraints, such as its inadequate solubility in water and limited bioavailability. Balakumar et al[100] studied the solubility of rosuvastatin in several excipients, such as oils, surfactants and cosurfactants, and they reported that among various surfactants, rosuvastatin displayed the greatest solubility. For bioavailability, the authors juxtaposed the results from the in vitro dissolution study with findings from an in vivo investigation in male Wistar rats and defined the plasma concentration-time following either a single oral dose of the CN7 self-nanoemulsifying drug delivery system (SNEDDS) or the drug in suspension. Thus, the outcomes demonstrated a noteworthy enhancement in the bioavailability of rosuvastatin with the SNEDDS formulation compared with the suspension. Consequently, utilizing a topical drug delivery system has emerged as a feasible substitute for oral rosuvastatin in the context of wound healing.

Hosny et al[92] reported that nano emulsions, as drug delivery systems that are formed from tiny droplets enclosed by a surfactant layer, may offer numerous advantages over traditional emulsions. First, it can increase drug solubility and bioavailability and achieve controlled drug release. Moreover, nano emulsions shield drugs from hydrolysis and enzymatic degradation, thus enhancing drug loading. Finally, the ability to cover a large interfacial area effectively targets specific actions.

Consequently, topical administration presents advantages over the oral route for wound repair. Gastrointestinal complications may be avoided, and side effects can be minimized[101]. Additionally, when a drug is topically delivered, it can cover a larger body surface area and effectively accelerates the healing process with enhanced epithelialization and minimal inflammatory cell infiltration[102].

The efficacy of rosuvastatin on wound healing in recent experimental studies is shown in Table 3[1,2,5,6].

Table 3 Efficacy of rosuvastatin on wound healing in recent experimental studies.

Ref.	Subjects	Intervention	Groups	Outcome
Santana et al[1], 2025	8 male New Zealand rabbits	Dermal wounds, RSV gel, autologous PRP 32 biopsies	The autologous PRP, RSV, PRP + RSV, control	PRP + RSV has higher collagen I than control
Marneri et al[2], 2024	36 male Wistar rats	Burn trauma, RSV topical	RSV, control (placebo)	RSV higher fibroblast proliferation, angiogenesis, re-epithelization, lower tumor necrosis factor-α, procalcitonin
Zaki et al[5], 2022	30 male Wistar rats	Skin wounds RSV transe-hosomal	Silver sulp-hadiazine RSV-loaded gel control	Nanovesicles enhanced wound healing
Salem et al[6], 2022	30 female Wistar rats	Skin wounds	RSV nano-cubics 16 mg plus RSV 1.4 mg/g hydrogel alone RSV or AgNPs or gentamicin control	Biogel RSV plus AgNPs enhanced wound healing

AgNPs: Silver nanoparticles; PRP: Platelet-rich plasma; RSV: Rosuvastatin.

CONCLUSION

Statins have a beneficial effect on wound healing. Both the dose and type of statin could influence the clinical outcome. However, because of its infrequent use in burn care, there are no reliable critical comparisons between different available studies. Additionally, the existing evidence supporting the potential beneficial effect of rosuvastatin on wound healing relies primarily on animal studies with small sample sizes and short-term follow-up. Despite the encouraging preclinical data, the use of statins in wound and burn healing is not widespread. Clinical studies are limited and heterogeneous. Rosuvastatin could be a potential alternative therapeutic approach for burn treatment, but the lack of large, well-designed randomized clinical trials is a significant limitation in the ability to draw definitive conclusions. Further experimental studies are recommended, followed by multicenter clinical trials, to confirm the findings and evaluate the potential for integrating statin therapy into everyday clinical practice.