Therapeutic Potential of Carnosic Acid in Alopecia: A Mechanistic Perspective

Keywords

alopecia - carnosic acid - Lamiaceae Rosmarinus officinalis - Salvia officinalis antioxidant - anti-inflammatory - anti-androgenic - hair follicle regeneration

Introduction

Alopecia, a common dermatological disorder characterised by partial or complete hair loss, affects individuals of all ages and genders, significantly impacting their psychological, emotional, and social well-being [1]. The condition manifests in various forms, including androgenetic alopecia (AGA), alopecia areata (AA), telogen effluvium (TE), and scarring alopecia, each with distinct aetiologies ranging from genetic predisposition and hormonal imbalances to autoimmune dysfunctions and environmental stressors. Despite the availability of FDA-approved treatments such as topical minoxidil and oral finasteride, the efficacy of these therapies remains limited, often accompanied by adverse effects like scalp irritation, sexual dysfunction, and poor patient adherence. This highlights the urgent need for safer, more effective therapeutic alternatives [2], [3].

In recent years, natural compounds have attracted considerable attention in dermatological research due to their diverse pharmacological properties and favourable safety profiles. Carnosic acid, a diterpenoid polyphenol found in plant species of the Lamiaceae family, primarily derived from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), has emerged as a promising therapeutic agent for the management of alopecia. Carnosic acid is recognised for its potent antioxidant, anti-inflammatory, anti-androgenic, and neuroprotective properties, which collectively contribute to its potential in modulating the pathophysiological mechanisms associated with hair loss. It has been shown to exert protective effects on hair follicle cells, mitigate oxidative stress, inhibit the release of pro-inflammatory mediators, and modulate androgen-related signalling pathways implicated in follicular miniaturisation [4].

This comprehensive review aims to elucidate the therapeutic potential of carnosic acid in alopecia management by exploring its pharmacological properties, mechanisms of action, and clinical relevance.

Methodology

This review was conducted to comprehensively evaluate the therapeutic potential and underlying mechanisms of carnosic acid in the management of alopecia. A systematic literature search was carried out using multiple electronic databases including PubMed, Scopus, ScienceDirect, and Google Scholar to retrieve relevant studies published up to December 2024. The search strategy involved combinations of the following keywords: “carnosic acid”, “alopecia”, “hair loss”, “Rosmarinus officinalis”, “Salvia officinalis”, “antioxidant”, “anti-inflammatory”, “anti-androgenic”, “hair follicle regeneration”, and “neuroprotective effects”. Inclusion criteria encompassed peer-reviewed original research articles, in vitro and in vivo studies, clinical trials, and comprehensive reviews that discussed the pharmacological properties of carnosic acid in the context of hair growth and alopecia management. Articles not published in English, abstracts without full-text access, and studies lacking relevance to carnosic acid or alopecia were excluded. Relevant information was extracted on the chemistry, pharmacokinetics, pharmacodynamics, and biological activities of carnosic acid, particularly in relation to oxidative stress, inflammation, androgen signalling, follicular regeneration, neuroprotection, and microbial effects. Data were synthesised qualitatively to elucidate mechanistic insights and therapeutic implications. Figures, tables, and mechanistic models were developed based on findings from high-quality primary studies to enhance clarity and comprehensiveness.

Alopecia

Alopecia is a pathological condition characterised by the loss or absence of hair from areas of the body that typically support hair growth, such as the scalp and other body regions. The mechanism of hair loss is depicted in [Fig. 1]. This condition can be distressing for patients, often leading to a decline in self-esteem and negatively impacting both psychological and social well-being [5]. Alopecia can manifest in various forms, including localised or diffuse, and it may be either temporary or permanent in nature. It can affect individuals of both genders and across all age groups [6]. Alopecia can result from various factors, as illustrated in [Fig. 2].

Fig. 1 Hair loss mechanism [7].

Fig. 2 Causes of alopecia [8].

Alopecia is recognised as one of the most prevalent dermatological conditions, ranking as the second most common social disease, and is associated with significant impairments in psychological health and overall quality of life for affected individuals [9]. The condition is broadly classified into two primary categories: cicatricial alopecia, also known as scarring alopecia, and non-cicatricial alopecia, or non-scarring alopecia. Cicatricial alopecia refers to a group of disorders characterised by the permanent destruction of hair follicles, leading to irreversible hair loss. Cicatricial alopecia can be further subdivided into primary and secondary forms. In contrast, non-cicatricial alopecia is generally reversible and represents the most common type of alopecia [10]. The classification and types of alopecia are presented in [Table 1].

Table 1 Classification and types of alopecia.

Classification	Type	Description	Causes	Signs & Symptoms	References
Non-Scarring Alopecia	Androgenetic Alopecia (AGA)	A genetic and dermatological condition, also known as male pattern baldness, leading to progressive hair loss.	Miniaturisation of hair follicles caused by androgens.	Thinning hair, receding hairline, scalp itching, sticky texture.	[11], [12]
	Alopecia Areata (AA)	An autoimmune, chronic, relapsing disorder that causes bald patches on hair-bearing areas of the body.	Loss of immunity in hair follicles, activation of JAK/STAT signalling pathway.	Hair loss, anxiety, scalp itching, small dents in nails.	[13], [14]
	Loose Anagen Syndrome (LAS)	A painless condition where hair is easily plucked during the anagen phase, with structural abnormalities in the inner root sheath.	Structural defects in the inner root sheath.	Hair loss, frizzy and matted hair, sticky, fine or short hair.	[15], [16]
	Short Anagen Syndrome (SAS)	Characterised by an increased number of hair follicles in the telogen phase, leading to diffuse short hair.	Shortened anagen phase and increased telogen follicles.	Short, fine hair that does not grow long.	[17], [18]
	Telogen Effluvium (TE)	A diffuse form of hair loss affecting less than 50% of the scalp.	Hormonal imbalances, stress, nutritional factors, drug use.	Hair loss, anxiety, thinning hair.	[19], [20]
	Tinea Capitis (TC)	A fungal infection caused by dermatophytes, mainly Microsporum and Trichophyton species.	Infection of the hair and scalp by dermatophytes.	Hair loss, scalp scaling, grey patches, black dots, erythema, crusts, impetigo-like lesions.	[21]
Scarring Alopecia	Frontal Fibrosis Alopecia (FFA)	A progressive inflammatory condition resulting in the slow recession of the front temporal hairline.	Cytotoxic inflammatory attack leading to reduced epithelial hair follicle stem cells (HFSCs) and epithelial-mesenchymal transition.	Receding hairline, eyebrow loss, scalp discomfort, skin changes, bumps.	[22]
	Lichen Planopilaris (LPP)	Lymphocytic cicatricial hair loss disorder causing patches of hair loss on the scalp, often accompanied by intense itching and inflammation.	Cytotoxic inflammation affecting HFSCs and epithelial-mesenchymal transition.	Hair loss, redness, irritation, bumps, pain, itching, burning sensation.	[23], [24]
	Keratosis Follicularis Spinulosa	A progressive scarring alopecia affecting hair, eyelashes, and eyebrows, typically inherited.	X-linked dominant and X-linked recessive inheritance.	Hair loss, skin changes, eye issues, allergic reactions.	[25]
	Central Centrifugal Cicatricial Alopecia	A progressive form of scarring alopecia starting at the crown and spreading outward.	Chronic inflammation leading to degeneration of the outer root sheath.	Hair loss, itching, pain, tenderness, burning, bumps.	[26], [27]
	Erosive Pustular Dermatosis of the Scalp	An inflammatory condition with sterile pustules and chronic crusted erosions on the scalp.	Autoimmune condition.	Hair loss, pustules, shallow erosions, thick crusts, skin atrophy.	[28], [29]

Carnosic Acid: Chemistry and Pharmacological Profile

Chemistry

Carnosic acid (CA) is a naturally occurring phenolic diterpene classified within the abietane-type diterpenoid family. It is primarily found in R. officinalis (rosemary) and S. officinalis (sage), where it serves as a chief bioactive compound responsible for the antioxidant and pharmacological properties of these plants [30], [31]. Structurally, carnosic acid is characterised by a catechol moiety ([Fig. 3]), which contributes to its potent radical-scavenging activity [31].

Fig. 3 Structure of carnosic acid.

The molecular formula of carnosic acid is C₁₈H₂₈O₄, with a molecular weight of 332.43 g/mol. Its core structure consists of a tricyclic diterpene backbone with hydroxyl (-OH) and carboxyl (-COOH) functional groups, which influence its solubility, reactivity, and pharmacokinetic profile [30], [32]. The presence of hydroxyl groups at positions C₁₁ and C₁₂ enables carnosic acid to undergo redox cycling, contributing to its ability to neutralise reactive oxygen species (ROS) [33]. The physicochemical properties of CA are summarised in [Table 2].

Table 2 Physicochemical properties of carnosic acid [30], [34], [35].

Property	Standard values
Drug Name	Carnosic acid
Chemical Name	5,6-dihydroxy-1,1-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthrene-4a-carboxylic acid
Molecular Formula	C18H28O4
Molecular Weight	332.43 g/mol
Melting Point	190 °C–201 °C
Boiling Point	506.4 °C at 760 mmHg
Density	1.184 g/cm³
Appearance	Yellow
Log P	5.405
pKa	4.14
BCS Class	Class II
Solubility	Slightly soluble in chloroform and methanol
Half-life	Approximately 3.5 hours
Physical State	Solid
Absorption	Well absorbed in the bloodstream following oral administration
Distribution	Well distributed in the intestine, liver, and muscle tissues
Metabolism	Hepatic
Excretion	Urinary

CA is biosynthesised through the mevalonate (MVA) pathway, starting from geranylgeranyl pyrophosphate (GGPP), a common precursor for diterpenoids. The oxidation and rearrangement of diterpenoid intermediates lead to the formation of carnosic acid, which exists in equilibrium with its oxidised derivative, carnosol [31], [32].

Pharmacological activities

Carnosic acid exhibits a wide spectrum of pharmacological activities, including potent antioxidant, anti-inflammatory, anticancer, neuroprotective, antidiabetic, antimicrobial, and anti-obesity properties. These diverse therapeutic effects highlight its potential as a promising agent for the prevention and treatment of various diseases [33]. The major pharmacological activities of carnosic acid are summarised in [Table 3].

Table 3 Pharmacological applications of carnosic acid and corresponding activities.

S. No.	Pharmacological activity	Mechanism	References
1	Skin protectant	Protects skin from UV-induced damage (burns, hyperpigmentation) by mitigating oxidative stress and inflammation.	[36], [37], [38], [39]
2	Anticancer	Inhibits melanoma progression by reducing tumour number, size, and weight, while extending latency periods; possibly through apoptosis induction and anti-proliferative effects.	[40], [41]
3	Antifungal	Inhibits growth of fungal species (e. g., Candida, Aspergillus, and Cryptococcus) by compromising cell membrane and cell wall integrity.	[42]
4	Anti-inflammatory	Reduces the secretion of allergic inflammatory mediators and nitric oxide production in activated macrophages, thereby alleviating conditions such as atopic dermatitis.	[43], [44]
5	Anti-aging	Delays age pigment accumulation, reduces amyloid beta-induced paralysis, and upregulates longevity-associated genes, contributing to cellular and organismal longevity.	[45]
6	Antipyretic	Enhances blood circulation which aids in reducing fever.	[46], [47]
7	Wound healing	Supports wound healing through anti-inflammatory and antioxidant effects, although it may modulate cell proliferation and migration in a context-dependent manner.	[48], [49]
9	Anti-alopecia	Protects hair follicles from damage induced by androgens or environmental pollutants, potentially mitigating hair loss.	[50], [51]
10	Antioxidant	Neutralises free radicals, prevents lipid peroxidation, and minimises the formation of harmful byproducts (e.g., malondialdehyde) that contribute to cell damage and inflammation.	[52], [53]
11	Immunomodulatory	Inhibits activation of inflammatory signalling pathways (e. g., NF-κB) and downregulates pro-inflammatory cytokines (IL-6, TNF-α, IL-13), leading to reduced chronic inflammation.	[54], [55]
12	Antibacterial	Disrupts bacterial cell membranes, inhibits key enzymes, and interferes with DNA/protein synthesis, leading to bacterial cell death or growth inhibition.	[56]
13	Analgesic	Reduces pain indirectly by decreasing the production of pro-inflammatory cytokines and mediators (e. g., TNF-α, IL-6, and prostaglandins) that contribute to nociceptive signalling.	[57], [58]
14	Neuroprotective	Protects neurons from oxidative stress and reactive oxygen species, potentially preventing neuronal degeneration and related neurodegenerative conditions.	[59], [60]
15	Antilipidemic	Lowers total cholesterol, LDL-cholesterol, triglycerides, and fasting plasma glucose, while raising HDL-cholesterol levels, contributing to improved lipid profiles.	[61], [62]

Role of Carnosic Acid in Alopecia Management

Carnosic acid, a polyphenolic compound primarily found in R. officinalis, has gained attention for its potential role in alopecia (hair loss) treatment ([Fig. 4]). Compared to commercially available formulations such as minoxidil and finasteride, CA offers a multi-targeted, natural approach to alopecia management, exerting antioxidant, anti-inflammatory, and anti-androgenic effects, along with hair follicle regenerative potential. Unlike minoxidil and finasteride, CA acts on broader pathways including NF- κ B, Nrf2, Wnt/β-catenin, and JAK/STAT, potentially addressing not only hormonal but also oxidative and autoimmune triggers of hair loss. The role of CA in alopecia management is discussed in detail below.

Fig. 4 Mechanistic overview of carnosic acidʼs therapeutic effects in alopecia.

Antioxidant properties

Oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, has been implicated as a critical factor in the pathogenesis of androgenic alopecia (AGA) and other hair loss disorders [33]. CA, a potent natural antioxidant derived from R. officinalis, has demonstrated significant potential in mitigating oxidative stress-related hair follicle damage and promoting hair regrowth [50].

CA acts as a radical scavenger due to the presence of its catechol moiety, which consists of two O-phenolic hydroxyl groups at C11 and C12. Upon oxidation, CA undergoes an electron transfer reaction, neutralising ROS and preventing lipid peroxidation within cellular membranes [30]. A comparative analysis has shown that CA exhibits antioxidant activity superior to that of vitamin E (α-tocopherol) and synthetic antioxidants such as butylated hydroxytoluene (BHT), primarily due to its efficient radical-quenching properties [63], [64].

Oxidative stress-induced damage to hair follicle stem cells (HFSCs) leads to premature follicular miniaturisation, disrupted hair growth cycles, and eventual hair loss [65]. CA exerts protective effects on HFSCs by reducing oxidative burden, thereby preserving follicular integrity. Studies have demonstrated that CA modulates mitochondrial function by stabilising membrane potential and preventing excessive ROS accumulation, which is crucial for maintaining active hair follicle cycling [66].

A study by Kesika et al. [67] investigated the effects of rosemary extract, rich in CA, on hair growth in a testosterone-induced hair loss model. The study found that topical application of CA significantly increased the expression of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), both of which are critical for hair follicle angiogenesis and cell proliferation. This suggests that CA not only mitigates oxidative stress but also enhances dermal papilla cell viability, thereby promoting hair regeneration [68].

Inflammation is a secondary yet significant contributor to hair follicle damage in alopecia, often exacerbated by oxidative stress [69]. CA has been shown to inhibit the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathways, a key regulator of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [70], [71]. By downregulating inflammatory markers, CA helps create a more conducive microenvironment for hair follicle regeneration. A recent study by Wan et al. [72] demonstrated that CA supplementation reduced inflammation-induced ROS levels in animal models subjected to lipopolysaccharide (LPS)-induced oxidative stress. Since LPS exposure mimics chronic inflammatory conditions, these findings further substantiate CAʼs role in reducing inflammation-driven follicular degeneration in alopecia.

Anti-inflammatory properties

Alopecia, particularly androgenic alopecia (AGA) and alopecia areata (AA), is often associated with chronic inflammation and immune dysregulation in hair follicles. Inflammatory cytokines, oxidative stress, and immune-mediated mechanisms contribute to the progressive miniaturisation of hair follicles, disrupting the hair growth cycle and leading to hair loss [73]. CA exerts its anti-inflammatory effects through multiple molecular pathways, primarily by inhibiting pro-inflammatory cytokines and signalling cascades involved in hair follicle inflammation. The nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signalling pathways is a major regulator of inflammation and immune response in hair follicle cells. Dysregulated NF-κB activation is associated with increased production of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), which contribute to follicular inflammation and apoptosis of dermal papilla cells [74], [75], [76], [77].

Several studies have demonstrated that CA inhibits NF-κB activation, thereby reducing the expression of these cytokines. Guo et al. [78] reported that CA downregulated NF-κB and attenuated TNF-α and IL-6 levels in an inflammation-induced model, suggesting its potential in suppressing inflammatory responses that drive hair follicle damage in alopecia.

Alopecia areata (AA) is an autoimmune condition characterised by T cell infiltration and cytokine-mediated destruction of hair follicles. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways plays a critical role in AA pathogenesis by mediating the effects of interferon-gamma (IFN-γ) and other pro-inflammatory signals [79]. CA has been shown to modulate JAK/STAT signalling by inhibiting the phosphorylation of STAT1 and STAT3, reducing the transcription of inflammatory mediators involved in autoimmune responses [80]. This suggests that CA may be effective in preventing the T cell-driven hair follicle destruction seen in AA.

Chronic inflammation in alopecia is often exacerbated by oxidative stress, which activates inflammatory pathways, leading to hair follicle miniaturisation. CA acts as a potent antioxidant by ROS, thereby reducing oxidative stress-induced inflammation in hair follicle stem cells (HFSCs) [81].

Cyclooxygenase-2 (COX-2) is an enzyme responsible for the synthesis of pro-inflammatory prostaglandins, particularly prostaglandin D2 (PGD2), which has been implicated in AGA. Elevated PGD2 levels in the scalp inhibit hair follicle elongation and promote miniaturisation, leading to hair thinning [82]. CA has been shown to inhibit COX-2 expression and PGD2 production, thereby reducing inflammation-mediated hair loss. A study by Xue-Gang et al. [83] demonstrated that CA effectively downregulated COX-2 activity, suggesting a potential mechanism through which it may counteract PGD2-induced hair follicle miniaturisation in AGA. CD4+ T cells play a pivotal role in maintaining immune homeostasis and combating inflammatory diseases. The differentiation and regulation of T-helper (Th) cell subsets, including Th1, Th2, Th17, and T-regulatory (Treg) cells, are critical in autoimmune conditions such as alopecia areata. Dysregulation of these subsets, characterised by elevated levels of cytokines like IL-2, IFN-γ, TNF (Th1), IL-5, IL-6, and IL-13 (Th2), is associated with follicular damage and hair loss [84].

Anti-androgenic effects

Androgenic alopecia (AGA) is primarily driven by the hormone dihydrotestosterone (DHT), which induces miniaturisation of hair follicles. CA has demonstrated potential anti-androgenic properties by inhibiting DHT synthesis or its action, thus mitigating the progression of AGA.

The pathogenesis of AGA and AA involves NKG2D+ CD8+ T cells, which produce Th1 cytokine interferon-γ (IFN-γ), leading to an imbalance in hair follicle immune privilege. This immune dysregulation results in localised inflammation and apoptosis around hair follicles, ultimately causing hair loss. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), a non-toxic synthetic antioxidant with high water solubility and low molecular weight, effectively permeates biological membranes and mitigates oxidative stress, which is a contributing factor to hair follicle damage [85], [86].

Natural extracts of Notoginseng radix, particularly Panax notoginseng saponins (PNS), have garnered attention for their pharmacological activities, including promoting endothelial progenitor cell-mediated angiogenesis. Given that reduced follicular vasculature is a hallmark of hair loss, enhanced angiogenesis supports cyclic hair growth by meeting the increased nutritional demands of hair follicles during the anagen phase [87]. PNS also activates the Wnt/β-catenin signalling pathway, a critical regulator of hair follicle transition from the telogen to anagen phase [88], [89].

Hair follicle immune privilege is maintained through multiple mechanisms, including the downregulation of MHC class I molecules in the lower hair follicle, secretion of immunosuppressive factors such as TGF-β, IL-10, α-MSH, and MIF, and the expression of PD-L1 by perifollicular mast cells, which promotes regulatory T cell differentiation and immune tolerance. The extracellular matrix composed of mesenchymal cells also prevents immune cell infiltration, contributing to immune privilege maintenance [90], [91]. Steroidal 5α-reductase type 2 (SRD5A2) is pivotal in the pathogenesis of AGA. This membrane-bound enzyme, reliant on NADPH, catalyses the conversion of testosterone to DHT, which then forms a complex with androgen receptors (AR) to act as a transcription factor, promoting androgen-dependent hair follicle miniaturisation [92], [93].

The JAK/STAT signalling pathway is implicated in inflammatory and autoimmune conditions, including alopecia areata. JAK inhibitors (JAKi) like tofacitinib (TFB) inhibit this pathway, promoting hair regrowth and disease reversal. However, systemic administration of JAKi can cause severe adverse effects, making topical application preferable for non-life-threatening conditions such as alopecia [94], [95]. Metformin, through activation of the AMPK enzyme, modulates immune responses by inhibiting the JAK/STAT and mTOR pathways, thereby preventing T lymphocyte proliferation and differentiation into cytotoxic T cells, which are implicated in hair follicle destruction in alopecia areata [96], [97], [98].

Hair follicle regeneration

Hair growth is driven by the vigorous proliferation of hair matrix keratinocytes and their subsequent differentiation as they migrate towards the surface of the scalp. Dermal papilla cells, specialised mesenchymal cells located beneath the hair matrix, play a critical role in regulating hair follicle (HF) differentiation, proliferation, and the hair growth cycle [99]. Recent studies have demonstrated that CA can enhance the activity of dermal papilla cells, which are essential for hair follicle regeneration and recovery from hair loss. This bioactive compound exhibits potential in stimulating hair growth by promoting cellular proliferation and enhancing follicular regeneration processes [93].

Under normal physiological conditions, the hair growth cycle is characterised by minimal immune cell presence around the anagen-phase HF bulb. However, in alopecia areata, the anagen phase is prematurely terminated due to an intense perifollicular and intrafollicular inflammatory infiltrate surrounding the HF bulb, histologically resembling a “swarm of bees”. This inflammatory response induces premature transition into the catagen phase, resulting in follicular dystrophy and apoptosis [100].

The presence of melatonergic receptors, particularly type 1 (MT1) and type 2 (MT2), in mammalian skin has been extensively documented [101]. MT1 receptors are expressed in key epidermal structures including hair follicles, fibroblasts, dermal papilla cells, and keratinocytes [102]. In contrast, MT2 receptors are predominantly localised in adnexal structures such as cutaneous blood vessels, eccrine glands, and the inner root sheath of the HF [103]. Dong et al. [104] utilised bromodeoxyuridine and 3H-thymidine double-labelling techniques to identify a population of stem cells within the follicular bulge region. These bulge stem cells, in synergy with dermal papilla cells, are essential for the self-renewal and cyclic regeneration of HFs. While typically quiescent, HF stem cells can be activated by injury or growth stimuli, leading to rapid proliferation and subsequent generation of transit-amplifying cells and postmitotic differentiating cells that contribute to wound repair and HF reconstruction [105].

Neuroprotective and stress-modulating effects

Carnosic acid supports hair growth not only through direct action on hair follicles but also by neuroprotective and stress-modulating mechanisms, by protecting neurons, modulating stress pathways, and maintaining a healthy scalp environment [106]. CA activates the Nrf2 (nuclear factor erythroid 2–related factor 2) pathway, enhancing the expression of cytoprotective and antioxidant enzymes such as HO-1, NQO1, and SOD, which protect hair follicle cells from oxidative damage, an important factor in hair follicle miniaturisation and alopecia [107]. It suppresses NF-κB signalling, reducing neuroinflammatory cytokines, which helps protect perifollicular nerves and maintain a healthy microenvironment around hair follicles. Peripheral innervation of hair follicles is crucial for cycling and regeneration. CAʼs neuroprotective actions may preserve this innervation by reducing oxidative stress and inflammatory insults, thus supporting normal hair cycling [108].

Chronic psychological or physiological stress elevates cortisol, which impairs hair growth by pushing follicles into the telogen (resting) phase. CA indirectly modulates the hypothalamic–pituitary–adrenal (HPA) axis, attenuating stress responses and thereby reducing cortisol levels or its local effects on dermal papilla cells [109], [110]. By reducing psychological stress, CA may prevent stress-induced hair loss, such as telogen effluvium or alopecia areata. CA has been reported to prolong the anagen (growth) phase of hair follicles, possibly by mitigating oxidative and emotional stress, preserving peripheral nerve function, and ensuring a favourable follicular microenvironment [111]. Via its vasodilatory and anti-inflammatory effects, CA may enhance scalp blood flow, improving nutrient and oxygen supply to hair follicles [112].

Antimicrobial activity

Carnosic acid exhibits broad-spectrum antimicrobial activity against bacteria, fungi, and viruses, making it a promising candidate for alopecia management, particularly in cases where microbial infections contribute to scalp conditions that exacerbate hair loss [112]. Extensive studies have demonstrated the efficacy of CA in inhibiting the proliferation of pathogenic bacteria, including Staphylococcus aureus and Propionibacterium acnes, both of which are implicated in scalp inflammation and follicular damage [113]. CA exerts both bacteriostatic and bactericidal effects against Gram-positive bacteria by disrupting bacterial membrane integrity and inhibiting biofilm formation. This mechanism is particularly relevant in folliculitis-associated hair loss, where CAʼs antibacterial properties may help prevent infection-induced follicular damage and subsequent alopecia [114].

Scalp disorders such as seborrheic dermatitis and tinea capitis, which are commonly associated with Malassezia species and Trichophyton fungi, respectively, contribute to significant hair shedding and follicular deterioration [115]. CA effectively suppresses fungal growth and inhibits hyphal formation, thereby reducing fungal colonisation on the scalp [116].

Safety and Toxicological Profile

Carnosic acid is classified as Generally Recognized as Safe (GRAS) by the U. S. Food and Drug Administration (FDA) when used as a food additive, indicating its established safety for human consumption in specified amounts [117]. Studies have demonstrated that CA exhibits low cytotoxicity in dermal cell lines at therapeutic concentrations. This suggests a favourable safety profile for potential dermatological and topical applications, with minimal adverse effects on skin cells [118]. Minimal skin irritation has been reported in topical formulations containing CA. Its anti-inflammatory properties may further contribute to reduced irritation, making it suitable for use in cosmetic and therapeutic products targeting skin and scalp conditions, including alopecia [112], [118].

Conclusion

This comprehensive review highlights the multifaceted therapeutic potential of CA, particularly in the management of alopecia. Its antioxidant, anti-inflammatory, anti-androgenic, and hair follicle-regenerative properties suggest its effectiveness in promoting hair growth and protecting against hair loss caused by oxidative stress, inflammation, and hormonal imbalances. Additionally, its neuroprotective and anticancer properties further reinforce its role as a promising bioactive compound for various therapeutic applications.

Despite its significant potential, challenges such as poor solubility and stability in conventional formulations limit its clinical translation. Therefore, advanced drug delivery strategies, such as nanostructured lipid carriers or encapsulation techniques, could be explored to enhance its bioavailability and efficacy. Future research should focus on well-designed clinical trials to validate its safety and effectiveness for alopecia treatment. Overall, CA presents a promising natural alternative to conventional alopecia treatments, offering a safer and potentially more effective approach.

Declarations

Human Ethics and Consent to Participate: Not applicable
Funding: None
Availability of data and materials: Not applicable

Authors contributions

PK and PS contributed significantly to the conception and design of the study. PS and MA were involved in data analysis and interpretation. AH supported in data collection. PS drafted the manuscript with input from all the authors. All authors reviewed and approved the final version of the manuscript.

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