Int. J. Biol. Sci. 2023, Vol.

19 4588

Ivyspring
International Publisher
International Journal of Biological Sciences
2023; 19(14): 4588-4607. doi: 10.7150/ijbs.86911
Review

Reversing Gray Hair: Inspiring the Development of New

Therapies Through Research on Hair Pigmentation and
Repigmentation Progress
Zhaorui Feng1,2#, Yi Qin1,2#, Guan Jiang1,2
1. Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
2. Department of Dermatology, Xuzhou Medical University, Xuzhou, China.

# These authors have contributed equally to this work.

 Corresponding author: Guan Jiang, Department of Dermatology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China. Email:
dr.guanjiang@xzhmu.edu.cn.

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.

Received: 2023.06.07; Accepted: 2023.08.19; Published: 2023.08.28

Abstract
Hair graying is a common and visible sign of aging resulting from decreased or absence of
melanogenesis. Although it has been established that gray hair greatly impacts people's mental health
and social life, there is no effective countermeasure other than hair dyes. It has long been thought
that reversal of gray hair on a large scale is rare. However, a recent study reported that individual
gray hair darkening is a common phenomenon, suggesting the possibility of large-scale reversal of
gray hair. In this article, we summarize the regulation mechanism of melanogenesis and review
existing cases of hair repigmentation caused by several factors, including monoclonal antibodies
drugs, tyrosine kinase inhibitors (TKIs), immunomodulators, other drugs, micro-injury, and tumors,
and speculate on the mechanisms behind them. This review offers some insights for further research
into the modulation of melanogenesis and presents a novel perspective on the development of
clinical therapies, with emphasis on topical treatments.
Keywords: hair repigmentation, hair pigmentation, melanogenesis, targeting drugs, topical treatments

Introduction
Hair graying is a common, visible, and early repigmentation imply the potential for systemic
marker of human aging [1, 2]. It is now understood behavioral factors (such as life stress) to
that human hair and its pigmentation can greatly simultaneously regulate the pigmentation of multiple
affect societal perception, emotional well-being, and HFs. Meanwhile, proteomics and computational
psychological state [3]. Considering the potential simulation have proven the theoretical possibility of
health risks posed by hair dyes [4], new strategies for reversing gray hair temporarily [5]. Based on the
hair color change are warranted. evidence presented, it becomes evident that the
Hair graying has long been thought of as an prevention or reversal of hair graying holds
irreversible age-related process. Nonetheless, recent significant promise for the future. Therefore, in this
research has revealed that restoring the color of a review, we summarize the regulation of melano-
single gray hair to its original pigmentation is a genesis and focus on cases of hair repigmentation and
general phenomenon regardless of age, gender, the mechanisms behind them, trying to inspire future
ethnicity, and corporeal regions but only appears in a research on the regulation of melanogenesis and
single anagen of rare HFs [5]. Although there is great therapy development.
heterogeneity between hair follicles (HF), the
similarities between the processes of graying and

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Overview of hair pigmentation and hair during a single anagen phase, the HFPU is
graying self-maintained and does not require replenishment
from McSCs [1]. Therefore, the initial onset of hair
Melanocytes in human HF are classified into graying is not necessarily related to the depletion of
several sub-populations according to function, McSCs. However, as individuals age, stranded McSCs
differentiation status, and location. Within anagen accumulate over time and do not contribute to the
hair follicles, melanocytes responsible for hair production of mature melanocytes [8, 16, 17]. The
pigmentation primarily reside in the hair matrix preservation of McSCs is crucial for the reconstruction
surrounding the mid to upper dermal papilla. These of the HFPU and provides the possibility for the
bulbar melanocytes express active tyrosinase and the reversal of grey hair. Once McSCs are exhausted, hair
melanogenic intermediate dihydroxyphenylalanine graying becomes irreversible [1].
(DOPA) and are considered a component of hair Epithelial stem cells (EpSCs) in the hair follicle
follicle pigment unit (HFPU) [1, 6]. Melanogenesis are crucial in providing a functional niche for
occurs in specialized lysosomal-related organelles melanocyte stem cells [18, 19]. The offspring of EpSCs
termed melanosomes. The melanin-containing in the HF bulge and hair germ develop into outer root
melanosomes are then transferred to the keratinocytes sheath (ORS) and transit-amplifying cells (TACs) in
of hair shaft through dendritic and filopodial the HF matrix, which support HF regeneration. The
processes [7]. Melanocyte stem cells (McSCs) are TACs differentiate into several lineages that
located in the bulge and the sub-bulge area of the eventually give rise to the hair shaft and its
outer root sheath (ORS). These cells are immature and supporting components [20]. Recently, single-cell
poorly or un-pigmented [6]. Recent studies have transcriptomics revealed that P53 pathway
indicated that the majority of melanocyte stem cells activation-induced specific depletion of matrix TAC,
possess a unique and unexpected mechanism for but not HFSCs, is associated with early-stage human
self-renewal and melanogenic melanocyte hair graying [20]. Therefore, the effects of regulatory
production. These McSCs exhibit a distinctive ability factors on cells within the HF, other than melanocytes,
to switch between transit-amplifying and stem cell are also considered in this context.
stages, which fundamentally distinguishes them from It is crucial to note that even visually colorless
other self-renewing systems [8]. According to live scalp HFs may still have a few hair bulb melanocytes.
imaging and single-cell RNA sequencing, McSCs Some may even continue to produce melanin,
move between the transit-amplifying and hair follicle although they lack dendritic morphology and
stem cell compartments through dedifferentiation, melanin transmission to the hair shaft [21]. Thus, it is
reversibly entering multiple differentiation stages theoretically possible that a special therapy that
controlled by the local microenvironment. Long-term reverses hair graying before all the hair bulb
lineage tracing studies have provided compelling melanocytes and McSCs disappear can be developed
evidence that the sustained melanocyte stem cell in the future.
system is supported by reverted McSCs that
dedifferentiate from transit-amplifying stage rather Signaling pathways in the regulation of
than reserved population of stem cells that inherently melanogenesis
maintained in an undifferentiated state.
Indeed, hair pigmentation and the hair cycle are Wnt/β-catenin signaling pathway
inextricably linked. The hair cycle consists of three When Wnt molecules bind to their receptors,
distinct stages: anagen, catagen, and telogen. Hair β-catenin is activated, increasing Melanocyte
pigmentation only happens during anagen because Inducing Transcription Factor (MITF) transcription in
the melanogenic HFPU exists in this period [9-11]. McSCs. Glycogen synthase kinase 3β (GSK3β)
Most differentiated melanocytes experience apoptosis phosphorylates β-catenin without Wnt signaling,
in the catagen phase, while bulge McSCs survive in which causes it to break down through a
the secondary hair germ [12-14]. As a new anagen proteasome-dependent mechanism. The activation of
phase is initiated, the surviving McSCs differentiate Wnt signaling also increases Endothelin Receptor
into melanogenic melanocytes to rebuild the HFPU Type B (EDNRB) signaling [22, 23]. These effects of
[13, 15]. Wnt signaling synergistically promote MsSCs’ migra-
Current evidence suggests that multiple factors tion, proliferation, differentiation, and melanogenesis.
can influence the process of hair graying [6]. Moreover, simultaneous activation of Wnt/β-catenin
However, the root cause of hair graying is the signaling in EpSCs and McSCs initiates pigmented
dysfunction and cell death of melanogenic hair regeneration [24].
melanocytes in the HFPU. It is widely thought that

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MC1R needed not only for the proliferation and survival of

As one of the central regulators of pigmentation, melanoblasts but also for Tyr induction and the
Melanocortin 1 Receptor (MC1R) signaling promotes transition of melanoblasts to mature melanocytes [33].
melanogenesis and melanosome transfer in EDN/EDNRB
melanocytes. Interestingly, it has been shown that
Endothelin receptor B (EDNRB) has been
ultraviolet B (UVB) induces keratinocytes to express
identified as playing indispensable roles in the
pro-opiomelanocortin (POMC), which is cleaved to
maintenance, proliferation, differentiation, and
release α-melanocyte-stimulating hormone (α-MSH)
migration of McSCs [22]. Besides, EDNRB signaling
and adrenocorticotropic hormone (ACTH), both
activates PLC/IP3/ signaling and ER Ca2+ release
ligands of MC1R [25]. MC1R activates adenylyl
[27]. Following SOCE, MITF expression significantly
cyclase and then increases cyclic adenosine
increases via the Ca2+/PKC/MAPK/p90 ribosomal
monophosphate(cAMP). One of the numerous effects
S6 kinase (RSK) pathway, the Mitogen- and
of cAMP, mediated by cAMP-dependent protein
stress-activated kinase 1 (MSK1)/CREB pathway, and
kinase A (PKA), is the phosphorylation of
the PKA/CREB pathway [34-36]. The expression of
cAMP-responsive element-binding protein (CREB),
EDNRB is regulated by MITF, suggesting EDNRB
which stimulates MITF transcription [26].
signaling and MITF expression form a self-reinforcing
Store‐operated Ca2+ entry (SOCE) is initiated
positive feedback loop that promotes melanocyte
upon endoplasmic reticulum (ER) Ca2+ release. The
proliferation and melanogenesis [25]. After wounding
Ca2+ binding ER membrane protein stromal
or UVR, Endothelin 1 (EDN1)/EDNRB signaling
interaction molecule 1 (STIM1) senses the Ca2+ store
enhances the proliferation and differentiation of
depletion and then oligomerizes and interacts with
McSC and increases the regeneration of epidermal
plasma membrane store-operated Ca2+ (SOC)
melanocytes [22, 35].
channel Orai1, leading to Ca2+ influx [27]. α-MSH-
induced cAMP stimulates ER Ca2+ release through PI3K/AKT
phospholipase C (PLC)/ inositol triphosphate (IP3) It is well-established that the phosphoinositide
signaling. Subsequently, STIM1 activates the plasma 3-kinase (PI3K) signaling pathway activates the
membrane-localized adenylyl cyclase 6 (ADCY6), serine/threonine-specific protein kinase (AKT) to
which acts independently of Orai1, to increase cAMP. increase GSK3β enzyme activity and prevent melano-
This positive feedback loop controlled by cAMP‐Ca2+ genesis [37]. MC1R can activate PI3K/AKT signaling
crosstalk further promotes the effects of α-MSH [28]. to produce a negative feedback effect on melano-
In addition to promoting melanogenesis in genesis and stimulate the extracellular release of
melanocytes, the activation of MC1R also enhances melanin, preventing oxidative stress, DNA damage,
the repair of Ultraviolet radiation (UVR)-induced and reduced survival [38]. Although SCF/c-KIT is an
DNA damage [29]. Besides, it has been reported that upstream signal for PI3K/AKT activation in
injury or UVB-induced epidermal migration of McSCs melanocyte and melanoma cells [39, 40], whether
also relies on MC1R signaling [30]. c-KIT has such a negative feedback loop remains to be
SCF/C-KIT demonstrated experimentally.
The stem cell factor (SCF)/tyrosine kinase TGF-β
receptor (KIT) signaling system plays a significant
Transforming growth factor-β (TGF-β) is the
role in melanogenesis. When SCF binds to its receptor
major regulator of McSCs maintenance, causing cell
c-KIT, it triggers the receptor's tyrosine kinase
cycle arrest, downregulation of MITF and
activity, which results in receptor phosphorylation.
melanogenic genes, which ultimately keeps McSCs in
As a result of the phosphorylation of c-KIT,
a state of immaturity and quiescence [41]. MITF and
mitogen-activated protein kinase (MAPK) is
its downstream genes are the main targets of TGF-β in
stimulated and then triggers the phosphorylation of
inhibiting melanogenesis [42-45]. The TGF-β/Smads
CREB, activating MITF [31]. An extracellular signal-
pathway negatively regulates the paired-box
regulated kinase (ERK) can be activated by c-KIT
homeotic gene 3 (PAX3), which works synergistically
signaling. While ERK signaling activates CREB to
with the SRY-Box Transcription Factor 10 (SOX10) to
promote melanogenesis, it has also been shown to
upregulate MITF, dependent on a cAMP-response
phosphorylate MITF, leading to its ubiquitination and
element (CRE) [46, 47]. Both TGF-β1 and TGF-β3 also
subsequent degradation, thus forming a feedback
downregulate MITF by activating ERK signaling to
loop in melanin regulation [32]. However, it cannot be
decrease melanogenesis [48, 49]. Lastly, but
ignored that the presence of MITF alone is not
importantly, TGF-β1 and TGF-β2 are recognized as
sufficient for Tyr expression and that KIT signaling is

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key catagen-inducing growth factors of HF [50, 51]. It of nucleotide excision repair [67]. In response to
has been demonstrated in melanoma cell lines that the reactive oxygen species (ROS), MITF positively
direct transcriptional target of TGF-β1-the Kruppel- regulates apurinic-apyrimidinic endonuclease 1
like transcription factor GLI2 not only suppresses (APE1), hypoxia-inducible factor 1 (HIF1α), and
MITF through PKA/cAMP signaling [52] but also Peroxisome proliferator-activated receptor gamma
directly downregulates tyrosinase-related protein 2 coactivator 1-alpha (PGC1α) to improve survival
(TRP2) by competitive inhibition of CREB [53]. capacity under oxidative stress [68-70].
It has recently been revealed that MITF enhances
MITF STIM1 expression transcriptionally [71], indicating
MITF is a critical transcriptional regulator of the presence of a positive feedback loop between
melanogenesis and McSC maintenance and STIM1 and MITF to promote the MITF-inducing effect
differentiation [26, 54]. MITF positively regulates of MC1R or EDNRB signaling.
pigmentation-associated genes to promote differen- MITF can be regarded as a final common
tiation-associated function and directly transactivates pathway in modulating the biological behavior of
promoters of three primary melanogenesis enzymes, McSC and melanocyte to some extent, as several
tyrosinase (TYR), tyrosine-related protein-1 (TYRP-1), external and internal factors converge on it through
and dopachrome tautomerase, also known as different intracellular signaling pathways, and their
tyrosine-related protein-2, TYRP-2 (-2) [55]. MITF also effects depend on downstream genes (Fig. 1).
upregulates genes contributing to melanosome
function, such as G Protein-Coupled Receptor 143 Novel mechanisms of hair pigmentation
(GPR143), SILV, and melanoma-associated antigens regulation
recognized by T cells (MART-1) or melanosome
transport such as Rab27 and Myosin5a (MYO5a) [55, Sympathetic nerves and sensory nerves
56]. It is widely acknowledged that HFs are
Furthermore, MITF plays a role in melanocyte innervated by sympathetic and sensory nerves [72].
proliferation. The capacity of MITF to increase Under stressful conditions, these sympathetic nerves
cyclin-dependent kinase 2 (CDK2) expression are hyperactivated and release noradrenaline in
highlights its functions as a pro-proliferative factor bursts, resulting in rapid McSC proliferation possibly
[57]. MITF also has been known to activate the mediated by β2 adrenergic receptors/AC/cAMP/
transcription of T-box transcription factor 2 (TBX2) PKA pathway. It has been shown that these sensory
[58], which inhibits senescence by repression of p21 nerves can provide Sonic Hedgehog (SHH) signaling
and p19 and participates in melanocyte growth and [73], which is required for the normal proliferation of
invasion [59, 60]. Furthermore, MITF directly melanocytes [74]. Then these McSC differentiate
upregulates cell cyclin-related genes cyclin B1 ectopically and migrate out of the hair bulge,
(CCNB1) and cyclin D1 (CCND1) and mitotic genes eventually causing the permanent depletion of McSC
such as polo-like kinase 1 (PLK1) [61]. and irreversible grey hair [75].
Several downstream genes of MITF promote cell
survival. MITF is the positive regulator of Neurotransmitters
anti-apoptotic factors B-cell-lymphoma 2 (BCL2) and Multiple neuropeptides released from intra-
baculoviral IAP repeat containing 7 (BIRC7) [62, 63] epidermal sensory nerves, such as calcitonin
and is involved in the regulation of the oncogenic gene-related peptide (CGRP), substance P (SP), and
hepatocyte growth factor receptor MET and the type vasoactive intestinal peptide (VIP), have been
III ribonuclease DICER, a necessary regulator of reported to regulate melanogenesis by acting on
microRNA processing, thereby performing its melanocytes directly or indirectly through immune
anti-apoptotic effects [64, 65]. It is widely thought that and inflammatory responses [76, 77]. In this context,
MITF mitigates DNA damage by increasing a group we will primarily focus on their direct effects on HFs
of repair genes, including DNA ligase I (LIG1), and melanocytes.
telomerase reverse transcriptase (TERT), essential CGRP exerts catagen-inducing effects on human
meiotic endonuclease 1 homolog 1 (EME1), Breast HFs and can maintain and restore hair follicle
Cancer 1 protein (BRCA1), and Fanconi anemia immune privilege (IP) via repression of MHC class I
protein A (FANCA) [66]. MITF transcriptionally antigen [78, 79]. Melanogenesis and melanocyte
regulates General transcription factor IIH subunit 1 dendricity is enhanced by certain CGRP-induced
(GTF2H1), which encodes the core component of keratinocyte-derived melanotrophic factors ex vivo
Transcription Factor IIH (TFIIH), and CDK7, which [80]. In mice, CGRP from sensory neurons increases
encodes TFIIH kinase to promote the rapid recovery insulin-like growth factor-I (IGF-I) production in the

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Int. J. Biol. Sci. 2023, Vol. 19 4592

HF dermal papilla cells, thereby promoting hair Moreover, excess SP induced by mental stress
growth and melanogenesis [81]. However, not all decreases melanogenesis through keratinocytes.
studies support the conclusion that CGRP promotes During this process, the hypothalamic-pituitary-
melanin production. In this regard, it has been shown adrenocortical (HPA) axis is key in mediating the
that in B16F10 cells, CGRP cooperates with SP to effects of SP signaling [90]. However, contrasting
inhibit melanogenesis and induce cell apoptosis [82]. studies revealed that SP promotes EDN1 secretion via
SP is released from sensory nerve endings endothelin-converting enzyme 1 and upregulates
induced by psychoemotional stress and regulates Wnt/ β-catenin signaling by downregulating the Wnt
immune cells or HF mainly through neurokinin-1 inhibitor Dickkopf-1 (DKK1) to increase melano-
receptors (NK1R) [83, 84]. In organ-cultured HFs, SP genesis in normal human melanocyte ex vivo [91, 92].
upregulates nerve growth factor (NGF) and its Interestingly, the results from animal models present
apoptosis- and catagen-inducing receptor (p75NTR), a paradoxical outcome. These contradictory results
while it downregulates the growth-inducing NGF may be due to heterogeneity between cells and
receptor neurotrophic tyrosine kinase receptor type 1 different concentrations of SP.
(TrkA). Furthermore, MHC class I and β2-microglo- It is well-established that VIP, an immunoinhi-
bulin are upregulated, suggesting that SP impairs bitory neuropeptide secreted from perifollicular
immune privilege (IP) [84]. Animal models have also sensory nerve endings, prevents the HFs from IP
shown that stress-induced SP not only inhibits HF collapse [93] and promotes melanogenesis in the
keratinocyte proliferation and induces apoptosis but B16F10 cell line and normal human melanocytes
also promotes mast cell degranulation, causing the basically by activating the PKA/CREB/MITF
production of ROS and neurogenic inflammation, and signaling pathway [94].
then inhibits hair growth and induces the catagen
phase in the hair cycle [83, 85, 86]. Adipose tissue
Studies have shown that in B10F16 melanoma It has been shown that dermal white adipose
cells, SP not only exerts a synergistic effect with tissue (dWAT) is located underneath and partially
CGRP, but also induces apoptosis in B10F16 cells and integrated into the reticular dermis, surrounding HFs
downregulates 5-hydroxytryptamine (5-HT)1A [95]. Interestingly, there is a strong interaction
receptor and 5-HT2A receptor, both of which promote between HFs and dWAT [96]. HFs drive a cycle of
melanogenesis. This effect is mediated by binding to dWAT remodeling, where HFs secrete adipogenic
the NK1R receptor and activating S6 kinase 1 (S6K1) activators at the beginning of new hair growth, and at
while inhibiting the MAPK signaling pathway [87-89]. the end of hair growth, activator secretion decreases

Figure 1. Signaling pathways in the regulation of melanogenesis. Melanogenesis and melanocytes proliferation, differentiation and survival are regulated by the MITF
transcription factor, which is regulated by a number of important signaling pathways, including Wnt/β-catenin, KIT/SCF, ET-1/EDNRB, α-MSH/MC1R and TGF-β pathways. MITF:
Melanocyte Inducing Transcription Factor; GSK3β: Glycogen synthase kinase 3β; AKT: serine/threonine-specific protein kinase; MC1R: Melanocortin 1 Receptor; TGF-β:
Transforming growth factor-β; PI3K: phosphoinositide 3-kinase; SCF: stem cell factor; c-KIT: tyrosine kinase receptor; MAPK: mitogen-activated protein kinase; ERK:
Extracellular signal-regulated kinase; ET-1: Endothelin 1; EDNRB: Endothelin receptor B; PKC: Protein kinase C; α-MSH: α-melanocyte-stimulating hormone; cAMP: cyclic
adenosine monophosphate; PKA: cAMP-dependent protein kinase A; CREB: cAMP response element-binding protein; ACTH: adrenocorticotropic hormone; AC: adenylate
cyclase; PAX3: paired-box homeotic gene 3; SOX10: SRY-Box Transcription Factor 10; CRE: cAMP-response element.

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Int. J. Biol. Sci. 2023, Vol. 19 4593

or adipogenesis inhibitor secretion increases, leading important factors such as Wnt10B and the HGF
to lipolysis [95, 97]. dWAT is rich in growth factors receptor c-Met within the hair matrix and DP [103].
that signal reciprocally to HF and regulates the Meanwhile, neutralizing adiponectin isoforms within
activation state of their stem cells and the rate of hair HF and dWAT promotes melanocyte proliferation,
regeneration [95]. melanogenesis, and tyrosinase activity but produces
Importantly, mature dWAT can inhibit hair fewer melanocytes and dendrites. Nevertheless, hair
growth. During early telogen, HFs enter a refractory matrix keratinocyte proliferation and hair
phase to growth signaling, partly mediated by bone pigmentation were not altered by adiponectin
morphogenetic protein 2 (BMP2) expressed by oligomer within 48h ex vivo.
adjacent dermal adipocytes [97]. A large area of Adiponectin exists in two forms in circulation, a
dWAT expresses BMP2, which highly maintains the full-length protein and a fragment containing the
quiescence of HFSC to prevent excessive hair globular domain of adiponectin (gAd). The full-length
production [95]. adiponectin induces depigmentation via AMPK/
In contrast, dWAT in anagen positively affects CREB-regulated transcription coactivators (CRTCs)/
hair growth. Adipose progenitor cell is essential for CREB signaling pathway [104], but the gAd promotes
HF to enter a new anagen and is widely thought to melanogenesis by activation of the AMPK-p38
stimulate telogen HFs through high levels of platelet‐ MAPK-CREB pathway [105]. Hence, the proportion of
derived growth factor alpha (PDGFA) [95]. Hepato- adiponectin oligomer to globular adiponectin or HGF
cyte growth factor (HGF), secreted by anagen to adiponectin could determine the quantity of
perifollicular dWAT, stimulates Wnt/β-catenin synthesized melanin.
signaling in the hair matrix by inhibiting Wnt Adipose-derived stem cells (ADSCs) are an
antagonist frizzled-related protein 1 (SFRP1) as well important type of stem cell that can be isolated from
as upregulating WNT10B, thereby promoting adipose tissue. They are characterized by their ability
melanocyte maturation and pigmentation [98]. to differentiate into multiple cell types, ease of
Current evidence suggests that dWAT plays availability, high proliferative capacity, and self-
significant roles in the aging process of HF [99]. Aging renewal potential [106]. ADSCs exert their multiple
dWAT represses Wnt signaling by upregulating Wnt regulatory roles mainly through autocrine and
inhibitors dickkopf-related protein (DDK) and SFRP4. paracrine pathways [107].
Additionally, there is an increase in the expression of Besides producing various cytokines that
fibroblast growth factor (FGF)5 and BMP2, which promote hair growth, such as VEGF, PDGF, and HGF
inhibit hair growth, while the secretion of hair [108], ADSCs also secrete exosomes to regulate HF.
growth-promoting factors such as FGF10 and FGF7 is An increasing body of evidence suggests that
reduced. Compared with young dWAT, senescent adipose-derived stem cell exosome (ADSC-Exo)
dWAT in telogen expresses abundant abnormal enhance DPC proliferation and survival and promote
inflammatory factors. In aging dWAT during anagen, hair regeneration, mediated in part by inhibiting
the inflammatory process is largely suppressed, but TGF-β/SMAD3 signaling by miR-122-5p carried in
collagen production, angiogenesis, and melano- ADSC-Exo [109-111]. Moreover, ADSC-induced
genesis are impaired. amphiregulin promotes hair regeneration of
Given that melanogenesis and hair growth share skin-derived precursors (SKPs), a multipotent
common signaling pathways, it is highly conceivable precursor cell population from the dermis capable of
that dWAT regulates hair graying, although further differentiating into several lineages through
research is warranted to validate this hypothesis and activation of PI3K and MAPK pathways [112].
explore the underlying mechanisms. Stromal vascular fraction (SVF), the regenerative cell
Adiponectin, an adipocyte hormone, is cocktail obtained mainly from ADSCs, has also been
specifically and abundantly expressed in WAT. shown to treat alopecia areata effectively and safely
Adiponectin or activation of adiponectin receptor 1 [113].
(AdipoR1) can upregulate multiple hair growth In addition to promoting hair growth, ADSCs
factors through AMP-activated protein kinase are also a regulator of melanogenesis. Interestingly,
(AMPK) in human follicular DPC, including IGF-1, ADSCs can inhibit the proliferation and melano-
vascular endothelial growth factor (VEGF), IGF, HGF, genesis of epidermal melanocytes through an
PDGFA, and FGF 7, and downregulate TGFβ1, interleukin-6 (IL-6)-mediated mechanism [114] and
thereby inducing the anagen and promoting hair through upregulation of TGF-β1 [43]. UVB-induced
growth ex vivo and in vivo [100-103]. In contrast, ex vivo skin pigmentation is reduced in the area of the skin
studies revealed that adiponectin oligomer where ADSCs have been injected, possibly related to
downregulates pigmentation genes in HF and the fact that α-MSH/MCIR/cAMP signaling is

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suppressed by basic fibroblast growth factor (bFGF) repigmentation, suggesting it is a promising indicator
secreted from ADSCs [115-117]. It also has been of positive treatment response [127]. Besides, hair
reported that SVF can inhibit UVB-induced repigmentation of the entire body was reported in a
pigmentation in guinea pig skin [118]. male patient with concomitant advanced colorectal
Intriguingly, ADSCs have shown the potential to cancer and Hodgkin lymphoma who underwent
promote pigmentation in the context of vitiligo nivolumab treatment, an anti-PD-1 antibody [128]. It
treatment. ADSCs not only promote the proliferation is widely thought that PD-1/PD-L1 immunotherapy
and migration of co-cultured melanocytes and reduce and cytotoxic tumor destruction cause an
their differentiation [119] but also improve the inflammatory state, which results in the collapse of
effectiveness of melanocyte transplantation for the immune privilege of HF and hair repigmentation
vitiligo, likely because ADSCs upregulate bFGF and [129]. It has also been reported that melanogenesis-
SCF and then increases the expression of integrins in related genes and melanin production in B16F10 cells
melanocyte [120, 121]. Ex vivo, adipose tissue was downregulated by PD-L1 from polyinosinic-
extracellular fraction (AT-Ex) induces melanocyte polycytidylic-treated HaCaT cell [130], which
intracellular antioxidant enzymes via acting on suggests the direct relationship between PD-1/PD-L1
nuclear factor (erythroid-derived 2) -like (Nrf-2) to and melanogenesis. However, vitiligo is a common
counteract oxidative stress, promotes cell immune-related adverse event in ICIs treatment for
proliferation, and inhibits GSK3β to activate melanoma patients [131], possibly due to the
Wnt/β-catenin signaling [122]. Similarly, mice models induction of an anti-melanocyte response, which has
revealed that NB UVB/ADSCs transplantation not been observed in lung cancer patients [132].
combination therapy could improve oxidative stress Moreover, positive staining of anti-PD-L1 antibodies
and calcium homeostasis by stimulating Nfr2/ heme was found in a canities subita patient who
oxygenase (HO -1) signaling, causing vitiligo experienced extreme trauma [133]. Considering these
repigmentation [123]. contradictory evidences, more research must be done
While there are some inconsistencies in the to clarify the confusing relationship between
studies mentioned above, it is plausible to speculate melanogenesis and PD-1/PD-L1.
that ADSCs may promote the proliferation and Dupilumab, a monoclonal antibody for
survival of melanocytes by reducing inflammation interleukin 4 (IL-4) receptor alpha subunit, blocks the
and maintaining melanocyte quiescence. IL-4/IL-13/IL-4R axis and reduces T helper 2 (Th2)
cell response effectively [134]. Hair repigmentation
Cases of gray hair repigmentation and has been reported in an atopic dermatitis patient
possible mechanisms treated with dupilumab [135]. It has been revealed
that IL-4 suppresses the expression of MITF, TYRP-1,
Therapeutic monoclonal antibodies and DCT through the Janus Kinase 2 (JAK2)/ Signal
Monoclonal antibodies (mAbs), which are Transducer And Activator Of Transcription 6 (STAT6)
immunoglobulins, can target a specific epitope on an signaling pathway and then inhibits melanogenesis in
antigen and have emerged as an important class of human normal melanocytes (HNMs) [136].
therapeutic drugs. To date, numerous mAbs have As a tumor necrosis factor (TNF) inhibitor,
received marketing approval [124]. adalimumab is indicated to treat inflammatory
A cell surface receptor called programmed disorders, including psoriasis, rheumatoid arthritis,
death-1 (PD-1) acts as a T cell checkpoint and is and inflammatory bowel disease. There has been a
critical in controlling T cell exhaustion. When PD-1 reported case of hair repigmentation in a rheumatoid
binds to its ligand programmed death ligand 1 arthritis patient treated with adalimumab [137].
(PD-L1), this triggers a downstream signaling TNF inhibits melanogenesis and the viability of
pathway that suppresses T cell activation. melanocytes through multiple pathways and is
Tumor immune evasion is mediated by intricately connected with the pathogenesis of vitiligo
abnormally elevated PD-L1 expression on tumor cells [138]. It has been revealed that both TNF and IL-17
and antigen-presenting cells in the tumor microen- treatment of melanocytes downregulated c-KIT,
vironment [125]. Anti-PD-1/PD-L1 antibodies, one of MC1R, MITF, DCT, and other melanogenesis-related
the immune checkpoint inhibitors (ICIs), restore the genes, and the levels of tyrosinase and melanin
immune response to cancer cells by rescuing T cells significantly decreased [139]. The combined action of
from an exhausted state, which have been approved TNF and IL-17 has been shown to inhibit
for treating multiple malignancies [126]. melanogenesis through the PKA and MAPK signaling
A series of 14 patients undergoing anti-PD1/ pathways [140]. TNF and IL-17 have been found to
anti-PD-L1 therapy for lung cancer demonstrated hair induce the expression of β-defensin 3 in cultured

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keratinocytes. Acting as an antagonist for MC1R, melanocyte toxicity [138, 146].

β-defensin 3 can inhibit the activation of adenylate However, due to the high complexity of the
cyclase and tyrosinase induced by α-MSH [139]. Other body, TNF may have dual effects on melanogenesis.
in vitro studies reveal that TNF-α could reduce There is an increasing consensus that TNF-α can
melanocyte-stimulating hormones receptor (MSH-R) stimulate endothelins (EDNs) and SCF secretion from
binding activity, MC1R expression, and the melanocytes and keratinocytes to cause skin
expression of a melanosomal protein gp87, promoters hyperpigmentation [147-149]. Additionally, TNF-α-
of melanogenesis [141, 142]. IL-6, an inhibitor of induced production of reactive oxygen species (ROS)
melanogenesis, was significantly elevated in human contributes to melanogenesis [150]. It is widely
normal human melanocytes treated with TNF-α, thought that Adalimumab may mitigate the high level
IL-17, and interferon-gamma (IFN-γ) [136, 138]. In of TNF-α in rheumatoid arthritis patients, resulting in
vitro, IL-6 decreases melanogenesis by reducing the hair repigmentation, but the underlying mechanism
transcription of MITF in melanocytes [143, 144] and warrants further research (Fig. 2).
blocking the paracrine function of keratinocytes and Hair pigmentation was observed in a patient
fibroblasts through the IL-6 / STAT3 / FGF2 pathway with plaque psoriasis undergoing treatment with
[145]. secukinumab [151]. Secukinumab is a fully human
In vitro, the expression of intracellular adhesion monoclonal antibody that targets interleukin-17A and
molecule-1 (ICAM-1) in melanocytes can be is utilized in the treatment of various autoimmune
upregulated by TNF-α, which may promote T diseases.
cell/melanocyte adherence and immunologic In addition to its synergistic effects with TNF,
cytotoxic damage, resulting in vitiligo [138, 146]. IL-17 suppresses melanogenesis through ROS-
Ample evidence suggests that TNF-α treatment dependent autophagic melanocyte apoptosis and
increases ROS in melanocytes and leads to stimulates keratinocytes to secrete IL-1β through the
nuclear factor-κB (NF-κB)/ROS/ NLR
Family Pyrin Domain Containing 3
(NLRP3)/caspase 1 pathway [152].
Similarly, the production of TNF-α and
IL-6 in keratinocytes and fibroblasts is
increased dramatically by IL-17A ex
vivo [153]. Further investigation is
needed to determine the actual impact
of IL-1β on melanogenesis when it
directly interacts with melanocytes. In
melanoma cell lines, IL-1β has been
shown to downregulate MITF
expression through the activation of
NF-κB, c-Jun N-terminal kinases
(JNKs), and microRNA-155 [154, 155].
Additionally, IL-1β has the ability to
induce apoptosis in melanocytes [156].
However, contrasting findings have
also been observed. It has been
discovered that IL-1β can upregulate
MC1R expression in normal human
melanocytes [142]. Furthermore, recent
Figure 2. The biological roles of inflammatory factors in melanogenesis. Inflammatory factors
research has indicated that IL-1β
including PGE2 and PGF2α promote melanogenesis by stimulating cAMP pathway. While IL-4 and IFN-γ inhibit partially mediates UVB-induced
melanogenesis through JAK-STAT pathway. TNF-α inhibits melanogenesis by suppressing the PKA, MAPK and
MC1R pathways in combination with IL-17. IL-1β inhibits melanogenesis through NF-κB, JNK and MAPK
melanogenesis by upregulating the
pathways. IL-6, elevated via TNF-α and IFN-γ, decreases melanogenesis by reducing the transcription of MITF expression of TYR and TRP1 in
in melanocytes. IL-4: interleukin 4; JAK: Janus Kinase; STAT: Signal Transducer And Activator Of melanoma B16 cells [157]. Nevertheless,
Transcription; IFN-γ: Interferon gamma; IL-6: interleukin 6; PKA: cAMP-dependent protein kinase A; MAPK:
mitogen-activated protein kinase; IL-17: interleukin 17; TNF-α: tumor necrosis factor alpha; MC1R: it is unquestionable that both IL-17 and
Melanocortin 1 Receptor; PGF2α: Prostaglandin F2α; PGE2: prostaglandin E2; cAMP: cyclic adenosine IL-1β are positively associated with the
monophosphate; NF-κB: nuclear factor-κB; JNK: c-Jun N-terminal kinase; IL-1β: interleukin-1β; MITF:
Melanocyte Inducing Transcription Factor; TRP-1: Tyrosinase related protein-1; TRP-2: Tyrosinase related progression and extent of vitiligo, likely
protein-2. due to autoimmune melanocyte death
[158-161].

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Interestingly, an increase in melanocyte reported [169]. Hair repigmentation has also been
abundance and a concomitant decline in pigmentation observed in a nilotinib-treated CML patient [170].
signaling was observed in psoriasis lesions known to Several cases of hair pigmentation following sorafenib
overexpress IL-17 and TNF [139]. It has been reported and erlotinib treatment for lung adenocarcinoma have
that speckled lentigines appeared in resolved been documented [171, 172]. Indeed, all these drugs
psoriatic plaques after treatment with biological belong to the class of tyrosine kinase inhibitors.
agents, such as scukinumab[162, 163]. The occurrence As the first protein tyrosine kinase inhibitor,
of lentigines may be attributed to the removal of imatinib inhibits Bcr-Abl, platelet-derived growth
inhibition on melanogenesis when TNF-α and IL-17 factor receptor (PDGFR), and c-Kit. It has been
are blocked. When these inhibitory factors are approved for treating Philadelphia-chromosome-
suppressed, melanocytes in resolved lesions may positive CML and gastrointestinal stromal tumors
produce excessive melanin, leading to the formation (GIST) [173]. Nilotinib and dasatinib are
of lentigines. The mechanism of hair repigmentation second-generation inhibitors developed to address
following treatment may share similarities with the imatinib resistance in CML [174]. In recent years,
development of skin lentigines. alternative mechanisms of nilotinib have been
Ustekinumab, an anti-interleukin IL-12/23 p40 discovered, such inactivation of p38 MAPK in
monoclonal antibody, induced hair repigmentation in microglial/astroglial cells and a myoblast cell line
a psoriasis vulgaris patient [164]. It is widely believed [175, 176], inhibition of the discoidin domain receptor
that activation of the TH17 pathway by IL-23 is the (DDR) in metastatic colorectal cancer cells [177], and
predominant mechanism involved in the patho- prevention of NF-κB activation in microglial cells
genesis of psoriasis. The survival and proliferation of [178] indicating there are more target points of
TH17 and TH22 cells depend on IL-23. IL-17, IL-22, nilotinib. It has been reported that nilotinib and
and TNF-α are produced by TH17 cells, and IL-22 is dasatinib promote melanogenesis in vitro. In HM3KO
produced by TH22 cells. Naive T cells are converted melanoma cells, nilotinib was found to upregulate
into TH1 cells by IL-12, which secretes IFN-γ and MITF and its downstream genes by activation of the
TNF-α [165]. Ustekinumab may lead to hair cAMP/PKA/CREB signaling pathway and
pigmentation by decreasing these inhibitors of decreasing the phosphorylation of AKT, which
melanogenesis (IL-17 and TNF-α). repressed the pigmentation process by inhibition of
Brentuximab vedotin is an antibody-drug GSK3β [179]. In B16F0 mouse melanoma cells,
combination commonly used to treat CD30+ nilotinib was found to increase ROS levels and
lymphomas. This conjugation binds to the CD30 ROS-induced JNK activation, thereby inducing TYR,
antigen on the surface of cells expressing CD30. Upon TRP1, and TRP2 [180]. Dasatinib has also been
absorption by the cell, the compound undergoes discovered to promote melanogenesis in human
proteolytic cleavage, releasing monomethyl auristatin normal melanocytes through ERK/CREB/MITF
E. Interestingly, a patient who underwent allogeneic signaling and possibly through phosphorylation of
hematopoietic stem cell transplantation and received p38 MAPK and JNK [181].
brentuximab vedotin as a trial for refractory chronic Sorafenib is a multiple-target tyrosine kinase
graft-versus-host disease (cGVHD) experienced hair inhibitor, inhibiting Raf1, VEGF receptors,
repigmentation [166]. CD30 signaling enhances the platelet-derived growth factor (PDGF) receptors, and
activation of TH1 and TH17 cells, leading to increased several other targets [182]. It has been shown that
production of INF-γ and IL-17A. Additionally, CD30 Sorafenib also upregulates MITF and melanogenesis
signaling promotes the secretion of TNF-α and IL-6 in the HM3KO melanoma cell line by repression of
through the activation of NF-κB [167, 168]. AKT and ERK pathway and increase of β-catenin via
Importantly, these cytokines (INF-γ, IL-17A, TNF-α, reduction enzyme activity of GSK3β [183].
and IL-6) are known to negatively regulate It has been established that erlotinib selectively
melanogenesis. The observed hair repigmentation inhibits epidermal growth factor receptor (EGFR) and
induced by brentuximab may be attributed to the can be used to treat several solid tumors [184].
elimination of these proinflammatory cytokines, Although EGFR signaling negatively affects
which allows for the restoration of normal UVR-induced melanogenesis [185, 186], it is highly
melanogenesis processes. conceivable that post-inflammatory hyperpigmen-
tation is caused by erlotinib-induced follicle
Tyrosine kinase inhibitors inflammation [171].
In a retrospective cohort study involving 133 It has been established that tyrosine kinase
chronic myeloid leukemia (CML) patients treated inhibitors (TKIs) have various cutaneous adverse
with imatinib, 9 cases of hair repigmentation were effects, with skin and hair depigmentation being

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Int. J. Biol. Sci. 2023, Vol. 19 4597

relatively common but hair repigmentation occurring macrophage-colony stimulating factor (GM-CSF), all
less frequently [187-189]. The exact mechanism by of which have promotive effects on melanogenesis
which TKIs promote hair repigmentation is not yet [193, 201, 209-213]. The hair repigmentation effects of
fully understood, although it is believed to be due in IMiDs are primarily attributed to their ability to
part to their ability to enhance melanogenesis. inhibit the elevated levels of melanogenic inhibitors
observed in multiple myeloma patients.
Immunomodulatory drugs
Two cases have been reported in which multiple Cyclosporine A (CsA)
myeloma (MM) patients experienced hair repigmen- Cyclosporine A, the first reported immunosup-
tation after receiving lenalidomide or thalidomide pressive drug to selectively inhibit T cells, mainly
treatment [190, 191]. These drugs, which are targets Th cells to achieve its therapeutic effect [214].
immunomodulatory drugs (IMiDs), are approved for CsA has been shown to induce hair repigmentation in
specific types of hematological cancers and psoriasis patients [215-217]. HF is an immediate target
autoimmune diseases. Protein cereblon (CBRN) is a of CsA, and hypertrichosis may be the most intriguing
member of the Lon protease family that plays a crucial and most common adverse effect of CsA [218]. In vitro,
role in mediating the anti-myeloma effects and CsA downregulates SFRP1 in DP, an inhibitor of the
teratogenicity of this class of IMiDs [192]. IMiDs have Wnt ligand, which activates the Wnt/β-catenin
been shown to decrease the production of TNF-α in pathway in HF and then induces hair growth [219].
human peripheral blood mononuclear cells (PBMCs) Therefore, cyclosporine may promote melanogenesis
by promoting the degradation of TNF-α mRNA, by activating the WNT pathway in melanocytes.
potentially through CBRN [192]. Additionally, IMiDs However, it is possible that CsA's immunosup-
have been demonstrated to reduce the expression and pressive properties and its ability to reduce cytokine
secretion of IL-6, which is known to be upregulated levels could contribute to hair repigmentation by
by TNF-α [193]. IMiDs also produce therapeutic inhibiting melanogenesis.
effects on several diseases by inhibiting TGF-β
[194-198]. It has also been reported that IMiDs reduce Other drugs
IL-1 and IL-1β in plasma [199]. What's more, IMiDs A study revealed that hair repigmentation
inhibit the activation of NF-κB by blocking the occurred in two patients (one case is myxedema coma,
degradation of inhibitor of NF-κB (IκB) proteins [200]. and the other is iatrogenic hyperthyroidism) after
TNF-α, IL-6, TGF-β, and IL-1β are all recognized receiving high-dose thyroxine treatment [220]. In
as inhibitors of melanogenesis [201]. The impact of organ-cultured normal human scalp HFs, TH
TNF-α and IL-6 on melanogenesis was previously enhances the proliferation of hair matrix
examined in the context of "Adalimumab," while the keratinocytes, inhibits their apoptosis, and induces
influence of IL-1β was discussed in relation to and prolongs the anagen phase through the
"Secukinumab." downregulation of TGF-β2, a key catagen-promoting
Moreover, it has been established that IL-10, growth factor [220, 221].
which activates the STAT-3 and PI3K/AKT/NF-κB It has been reported that T4 downregulates the
signaling pathways to protect primary melanocytes intrafollicular expression of clock genes (BMAL1 and
[202], is induced by IMiDs [192, 203]. PER1) after 24h, both of which inhibit anagen/
NF-κB signaling participates in both the prolong catagen and inhibit HF pigmentation [222].
stimulation and the suppression of melanogenesis. It Both T3 and T4 significantly promote melanogenesis
was reported that TNF-α, tumor necrosis factor of organ-cultured HF, the mechanism of which
superfamily member 14 (TNFSF14), and IL-1β induce possibly is independent of the hair cycle [221].
melanogenesis by activating NF-κB [204, 205]. Thyroid hormone signaling is related to many
However, other studies suggest that activation of pigmented dermatoses and hair disorders, such as
NF-κB mediates the facilitation of melanogenic vitiligo, melanocytic nevi, and alopecia areata [223,
activity from multiple sources, such as IL-18, Toll-like 224], indicating that thyroxine plays an important role
receptor 9 agonists, and UVR-induced-oxidative in hair pigmentation and maintaining the homeostasis
stress, indicating that the target genes involved in of melanocytes.
regulating melanogenesis may not be identical when Hair repigmentation was induced in a glaucoma
NF-κB signaling is activated [206-208]. patient treated with latanoprost, a prostaglandin F2α
Interestingly, in multiple myeloma patients, (PGF2α) analog [225]. It is now understood that iris
IMiDs increase the production of IFN-γ (an inhibitor pigmentation, eyelashes hypertrichosis, and
of melanogenesis) from T cells, and IMiDs hyperpigmentation are common adverse events [226].
downregulate VEGF, bFGF, and granulocyte It has been revealed that PGF2α and prostaglandin E2

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(PGE2) promote melanocyte dendrites formation and [243]. Although there are conflicting reports, estrogen
the activation of tyrosinase through cAMP/PLC is considered to have ER-mediated promotive effects
signaling [227-230]. Moreover, ex vivo, PGE2 promotes on melanogenesis in melanocyte ex vivo, [244] possibly
the delivery of filopodia and quantities of shedding by activation of the cAMP/PKA/MITF pathway [245,
spheroid granules in melanocytes (MCs) but does not 246]. Estrogen also induces melanogenesis indirectly
influence the morphology of keratinocytes [231]. via keratinocytes [244]. In vivo, high estrogen levels
Current evidence suggests that local application of enhance melanogenesis and cause skin
latanoprost activates HFs and encourages hair hyperpigmentation, such as melasma [247]. However,
growth, and bimatoprost, another PGF2α analog, has in vitro, tamoxifen was found to stimulate synthesis
been approved for treating eyelash hypotrichosis [232, and extrusion of melanin, with decreased cAMP but
233]. A murine model validated the stimulatory effect upregulated catalase expression in normal human
of PGF2α and latanoprost on follicular melanogenesis melanocytes, suggesting tamoxifen has a
and hair regrowth [234]. ROS-mediated promelanogenic effect on melanocytes
A retrospective study reported that hair [248]. In practical terms, one of the established
repigmentation occurred in 24 of the 62 Alzheimer's anti-cancer mechanisms of tamoxifen involves
patients receiving prolonged cholinesterase inhibitor increasing apoptosis through the generation of
therapy [235]. Solar light not only induces skin reactive oxygen species [249].
keratinocytes to secrete acetylcholine (ACh), which L-DOPA has been reported to induce hair
represses light-induced melanogenesis probably by pigmentation in 3 patients with Parkinson's disease
inhibiting cAMP/CREB/MITF signaling in [250]. In addition to being the intermediate of
melanocytes [236, 237] but also promotes expression melanogenesis, L-DOPA is also a bioregulatory
of AChE in keratinocytes through transcription factor molecule that positively regulates melanogenesis by
activator protein 1 (AP1) ex vivo [238]. What's more, upregulating TYR and MC1R and regulating several
during melanin production in melanocytes and cellular processes, such as cellular metabolism [251].
B16F10 melanoma cells, AChE is downregulated by These can be mediated by interacting with certain
increased cAMP/CREB signaling [237]. The above receptors or by non-receptor mechanisms.
findings suggest that ACh and AChE inhibitors are Nevertheless, a study revealed that dopamine
local negative regulators of melanogenesis, and there directly induced catagen in human scalp HFs ex vivo
is a negative feedback loop of ACh-melanogenesis- [252]. Thus, L-DOPA may not be a good choice for
AChE among melanocytes and keratinocytes to beauty lovers who desire pigmented hair.
maintain melanin homeostasis in the skin. Cerebrolysin is a low-molecular-weight
Nevertheless, it was recently reported that neuropeptide obtained from the porcine brain and has
phagocytosis mediated by the α7 nicotinic neuroprotective and neurotrophic effects similar to
acetylcholine receptor causes the skin keratinocyte to neurotrophic growth factors. It has been reported that
take up melanosomes in response to UV exposure in cerebrolysin causes hair repigmentation linked to
vitro [239]. Moreover, M4 receptor-KO mice exhibit Melan-A, also known as MART-1 reactivation, in 5
poor hair growth with no HF melanogenesis [240], neurological patients [253]. Besides, some
indicating that cholinergic signaling is indispensable neuropeptides, such as CGRP, SP, and VIP, enhance
for pigmentation. melanocyte proliferation and melanogenesis [80, 91,
It has been established that these AChE 94]. In addition, the p75 neurotrophin receptor
inhibitors work by increasing ACh in the nervous (p75NTR) regulates apoptosis in the external root
system to treat patients with Alzheimer's disease. sheath of the HF [254]. Therefore, cerebrolysin may
Several reports revealed that ACh enhances the cause hair repigmentation as a neurotrophin factor.
release of α-MSH from pituitary melanotropes and Meanwhile, given that melanocytes are derived from
nerve-induced pigmentation in lower vertebrates the neural crest, the neuroprotective effects of
[241]. In a similar vein, it is also possible that ACh cerebrolysin, which include preventing nerve cell
causes hair repigmentation in a neuroendocrine- apoptosis and promoting differentiation and migra-
dependent manner. Meanwhile, considering choli- tion, may also be beneficial for melanocytes [253].
nergic signaling has multiple effects on neural and As second-generation retinoids, etretinate and
intestinal stem cells [242], ACh likely plays a role in acitretin exert their effects by binding to retinoic acid
McSC homeostasis. receptors and retinoid-X receptors. Interestingly, in a
A case report has documented that hair study involving four patients, both etretinate and
repigmentation occurred in a breast cancer patient acitretin were found to induce hair repigmentation
who received treatment with tamoxifen, the first and curling [255-258]. It has been demonstrated that
selective estrogen receptor modulator, for 2.5 years an increased level of retinoic acid (RA) upregulates

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the C-KIT receptor and then sensitizes McSCs to in part, in melanocyte stem cells located in the hair
KIT-ligand, eventually leading to ectopic McSCs follicle bulge area is responsible for the narrowband
differentiation in the niche in vivo [19]. Although the UVB (NBUVB)-induced repigmentation of vitiligo
mechanism behind hair color change induced by [275]. Recent studies have also reported that the
etretinate and acitretin is not completely understood, Wnt/β-Catenin pathway is involved in hair
it is possible that their impact on retinoic acid regeneration and vitiligo repigmentation following
metabolism could be an alternate mechanism. micro-injury [276].
However, current research only suggests that As a form of injury, epilation activates McSCs to
etretinate and acitretin increase the telogen phase of regenerate follicular and epidermal melanocytes
the hair cycle and inhibit melanocyte proliferation through induced endothelin 3/endothelin type-B
through retinoid-X receptor signaling [259, 260]. receptor (EDN3/EDNRB) signaling, leading to skin
According to some reports, some plant extracts and hair hyperpigmentation [277].
have ability to prevent hair graying. Eriodictyon Overall, the mechanism of micro-injury-induced
angustifolium (Ea) is a plant that grows on the west hair repigmentation is closely related to the
coast of North America and has been used for many Wnt/β-Catenin and EDN3/EDNRB pathways.
years as a traditional medicinal herb by the indi-
genous population. Abundant flavonoids contained Tumor
in Ea extract, such as sterubin and Roughly ten cases have been reported
hydroxygenkwanin, seem to be active ingredients to documenting focal hair repigmentation occurring on
prevent and reduce hair graying [261, 262]. Although and around the area of scalp melanoma [278-287]. A
the target is not molecularly clear, sterubin appears to hypothesized model for this phenomenon involves
function by activating Wnt signal and reducing ROS two key cascades. The first cascade involves
[263], while hydroxygenkwanin relies on KIT infiltrating melanoma cells, directly delivering
signaling [264]. Polygonum multiflorum(PM) is a melanin to follicular keratinocytes [283, 287].
tranditonal Chinese medicine that has been However, histopathological examination revealed
experiencely used to treat early graying hair for a long that many hair follicles remain uninvaded by
time. PM extract has been proven to potentiate melanoma cells but still exhibit repigmented hair.
melanin synthesis by targeting on α-MSH and MC1R This leads to the second cascade, where benign bulbar
and reducing ROS production [265-267]. Besides Ea melanocytes are activated by paracrine factors (such
and PM, Pueraria lobata extract and its active as SCF) released by neighboring melanoma cells [283,
compound, puerarin, also have been reported to 287]. Immunostaining studies have confirmed the
prevent hair graying via the cAMP/MITF signaling presence of TGF-β1-expressing follicular epithelium
pathway [268, 269]. adjacent to highly TGF-β1-positive melanoma cells
[287], supporting this second cascade.
Micro-injury It has been reported that paraneoplastic
Hair repigmentation was observed in an syndrome caused by lung cancer could induce the
84-year-old woman after Mohs micrographic surgery darkening of hair and skin in several patients. The
and secondary intention wound healing [270]. potential mechanism may be that a high level of
Physical therapy, such as phototherapy and ACTH in the body promotes melanogenesis through
microneedle, has been used to treat pigmentation the MC1R signaling pathway [1, 288] (Table 1).
disorders and hair loss for years [271-273]. In response
to injury or UVB, HF-McSCs migrate to the epidermis, Conclusion
depending on MC1R signaling. Then they While widespread repigmentation of gray hair is
differentiate to produce protective pigmentation uncommon, the underlying mechanism remains an
against UV [30]. Except for the absence of important area of study. Understanding the
pigmentation, de novo regenerated hair follicles can’t regulatory mechanisms involved in hair follicle
be distinguished from regularly growing hair follicles. melanogenesis and melanocyte stem cells is essential
However, when mice are injured during the anagen, for developing potential clinical therapies to reverse
de novo regeneration of pigmented hair is seen. This gray hair. However, achieving this goal necessitates
phenomenon may be caused by the fact that, extensive research efforts. Given that the skin is an
stimulated by increased Wnt7a of the keratinocytes, accessible part of the body and the position of the HFs
McSCs that have been induced to migrate to the is relatively superficial, topical treatment will have
interfollicular epidermis by injury are integrated into great advantages in safety and effectiveness.
de novo regenerated hair follicles [274]. Moreover,
activation of the β-Catenin signaling pathway, at least

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Table 1. Cases of gray hair repigmentation and possible mechanisms

Cases possible mechanisms
Monoclonal Anti-PD-1/PD-L1 An inflammatory state caused by PD-1/PD-L1 immunotherapy and cytotoxic tumor destruction results in the
antibody drug therapy collapse of the immune privilege of the hair follicle and promotes hair repigmentation.
Dupilumab It removes IL-4/JAK2/STAT6 signaling pathway’s inhibition of melanogenesis.
Adalimumab It blocks TNF-α and IL-17 signaling and then gets rid of inhibition on melanogenesis.
Scukinumab It blocks TNF-α and IL-17 signaling and gets rid of inhibition on melanogenesis.
Ustekinumab It decreases TNF-α and IL-17 produced by TH17 and TH22 cells.
Brentuximab It blocks CD30 signaling in TH1 and TH17 and then decreased INF-γ, IL-17A, TNF-α and IL-6.
tyrosine kinase Nilotinib It increases melanogenesis through activation of cAMP/PKA/CREB/MITF signaling pathway and decreases AKT
inhibitors signaling.
It also elevates ROS and induces JNK activation to upregulate TYR, TRP-1, TRP-2.
Dasatinib It promotes melanogenesis through MAPK or JNK/ERK/CREB/MITF signaling.
Imatinib The reason may be similar to Nilotinib and Dasatinib’s.
Sorafenib It represses AKT and ERK pathway and increases β-catenin.
Erlotinib Post-inflammatory hyperpigmentation after erlotinib-induced follicle inflammation.
Immunomodulatory lenalidomide or They decrease inhibitors of melanogenesis and increase promotors.
drugs thalidomide

Immunosuppressant Cyclosporine A CsA downregulates SFRP1, an inhibitor of Wnt ligand, which in turn activates Wnt/β-catenin pathway and then
induces hair repigmentation.
Other drugs L-thyroxine TH inhibits TGF-β2 and promotes melanogenesis.
BMAL1 and PER1 are downregulated to prolong anagen.
Latanoprost PGE2 and PGF2α stimulate melanogenesis by cAMP/PLC signaling and promoting melanosome delivery in
melanocyte.
Promotes hair follicle growth.
Acetylcholinesterase Not clear but cholinergic signaling is necessary for melanogenesis. Ach also seems to increase α-MSH secretion and
inhibitor regulate stem cells.
Tamoxifen It induces ROS in melanocyte to stimulate melanogenesis.
L-DOPA It upregulates TYP and MC1R to enhance melanogenesis.
Cerebrolysin As a kind of neuropeptide, it causes melanogenesis linked to Melan-A as a kind of neuropeptide
Retinoids The impact of etretinate and acitretin on RA metabolism, which upregulates C-KIT receptor and leads to ectopic
McSCs differentiation, may be an alternate mechanism for hair color change
Mechanical Micro-injury It activates MC1R signaling, Wnt signaling and EDNRB signaling and then promotes melanogenesis.
stimulation
Tumor Scalp melanoma Melanoma cells directly deliver melanin to keratinocytes or secrete some factors to activate surrounding normal
melanocyte in a paracrine manner.
Lung cancer Paraneoplastic syndrome in lung cancer leads to high level of ACTH, which can stimulate MC1R signaling.

Just as topical minoxidil is commonly used to PKA: protein kinase A; CREB: cAMP responsive
treat hair loss, topical agents that stimulate melanin element-binding protein; SOCE: Store‐operated Ca2+
synthesis to reverse gray hair will have promising entry; ER: endoplasmic reticulum; STIM1: stromal
prospects if they can be developed in the future. interaction molecule 1; SOC: store-operated Ca2+;
Physical therapies such as photodynamic therapy and PLC: phospholipase C; IP3: inositol triphosphate 3;
microneedling are also viable options. However, all ADCY6: adenylyl cyclase 6; UVR: Ultraviolet
these treatments rely on the presence of a sufficient radiation; SCF: stem cell factor; MAPK: mitogen-
population of active McSCs. Therefore, maintaining a activated protein kinase; ERK: Extracellular
healthy population of McSCs is also an urgent signal-regulated kinase; RSK: ribosomal S6 kinase;
problem that needs to be addressed. MSK1: Mitogen- and stress-activated kinase 1; EDN1:
Endothelin 1; PI3K: phosphoinositide 3-kinase; AKT:
Abbreviations serine/threonine-specific protein kinase; TGF-β:
TKIs: tyrosine kinase inhibitors; HF: hair follicle; Transforming growth factor-β; PAX3: paired-box
DOPA: dihydroxyphenylalanine; HFPU: hair follicle homeotic gene 3; SOX10: SRY-Box Transcription
pigment unit; McSC: Melanocyte stem cell; ORS: outer Factor 10; CRE: cAMP-response element; TRP2:
root sheath; GSK3β: Glycogen synthase kinase 3β; tyrosinase-related protein 2; TYR: tyrosinase; TYRP-1:
MITF: Melanocyte Inducing Transcription Factor; tyrosine-related protein-1; DCT: dopachrome tauto-
EDNRB: Endothelin Receptor Type B; EpSCs: merase, also known as tyrosine-related protein-2,
epithelial stem cells; TACs: transit-amplifying cells; TYRP-2; GPR143: Protein-Coupled Receptor 143;
MC1R: Melanocortin 1 Receptor; UVB: Ultraviolet B; MART-1: Melanoma-associated antigen recognized
POMC: pro-opiomelanocortin; α-MSH: α-melanocyte- by T cells; MYO5a: Myosin5a; CDK2: cyclin
stimulating hormone; ACTH: adrenocorticotropic dependent kinase 2; TBX2: T-box transcription factor
hormone; cAMP: cyclic adenosine monophosphate; 2; CCNB1: cyclin B1; CCND1: cyclin D1; PLK1:

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polo-like kinase 1; BCL2: B-cell-lymphoma 2; BIRC7: drugs; CBRN: lon protease Cereblon; PBMSs:
baculoviral IAP repeat containing 7; LIG1: DNA ligase peripheral blood mononuclear cells; CRBN: Cereblon;
I; TERT: telomerase reverse transcriptase; EME1: IκB: inhibitor of NF-κB; TNFSF14: tumor necrosis
essential meiotic endonuclease 1 homolog 1; BRCA1: factor superfamily member 14; MM: multiple
Breast Cancer 1 protein; FANCA: Fanconi anemia myeloma; bFGF: basic fibroblast growth factor;
protein A; GTF2H1: General transcription factor IIH GM-CSF: granulocyte macrophage-colony stimula-
subunit 1; TFIIH: transcription factor IIH; ROS: ting factor; CsA: Cyclosporine A; INF-α: interferon-α;
reactive oxygen species; APE1: apurinic-apyrimidinic HFs: hair follicles; TH: thyroid hormone; PGF2α:
endonuclease1; HIF1α: hypoxia-inducible factor 1; Prostaglandin F2α; PGE2: prostaglandin E2; MCs:
PGC1α: Peroxisome proliferator-activated receptor melanocytes; AChE: Acetylcholinesterase; Ach:
gamma coactivator 1-alpha; SHH: Sonic hedgehog; Acetylcholine; AP1: activator protein 1; L-DOPA:
CGRP: calcitonin gene-related peptide; SP: substance Levodopa; p75NTR: p75 neurotrophin receptor; RA:
P; VIP: vasoactive intestinal peptide; IP: immune retinoic acid; HF-McSCs: hair follicle melanocyte stem
privilege; IGF-I: insulin-like growth factor-I; NK1R: cells; EDN3/EDNRB: endothelin 3/endothelin type-B
neurokinin-1 receptors; NGF: nerve growth factor; receptor; sHG: secondary hair germ; NBUVB:
p75NTR: apoptosis- and catagen-inducing receptor; Narrowband UVB; c-KIT: tyrosine kinase receptor.
TrkA: tyrosine kinase receptor type 1; 5-HT:
5-hydroxytryptamine; S6K1: S6 kinase 1; HPA: Acknowledgements
hypothalamic pituitary adrenocortical; DKK1: This work was supported by Affiliated Hospital
Dickkopf-1; NAS: N-Acetylserotonin; CRS: chronic of Xuzhou Medical University.
restraint stress; CUMS: chronic unpredicted mild
stress; GABA: Gamma-aminobutyric acid; DPC: Author Contributions
dermal papilla cell; dWAT: Dermal white adipose ZRF prepared the related literature, and was a
tissue; BMP2: bone morphogenetic protein 2; PDGFA: major contributor in writing the manuscript. YQ drew
platelet‐derived growth factor alpha; HGF: the pictures and wrote part of the manuscript. GJ
Hepatocyte growth factor; SFRP1: frizzled related provided direction throughout the preparation of this
protein 1; DDK: dickkopf related protein; FGF: manuscript, and made significant revisions to the
fibroblast growth factor; AdipoR1: adiponectin manuscript. All authors have read and approved the
receptor 1; AMPK: AMP-activated protein kinase; final manuscript.
VEGF: vascular endothelial growth factor; gAd:
globular domain of adiponectin; CRTCs: CREB- Competing Interests
regulated transcription co-activators; ADSC-Exo: The authors have declared that no competing
Adipose-derived stem cell exosome; SKPs: interest exists.
skin-derived precursors; SVF: Stromal vascular
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