50 No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025
VITAMIN D AND THE SKIN: FOCUS ON A COMPLEX RELATIONSHIP: A REVIEW
Shki yak A.
CEO and chie medical o ice “Shki yak Clinic”
Uk aine
Neu osu geon
MD, MsSc
ORCID: h ps://o cid.o g/0000-0002-2282-8285
Khanenko S.
“Shki yak Clinic”
Uk aine
Family doc o
MD, MBA
ORCID: h ps://o cid.o g/0009-0000-4237-1158
h ps://doi.o g/10.5281/zenodo.17608968
Abs ac
The “sunshine” i amin is a ho opic ha a ac ed ample a en ion o e he pas decades, specially ha a
conside able p opo ion o he wo ldwide popula ion a e de icien in his essen ial nu ien . Vi amin D was p i-
ma ily acknowledged o i s impo ance in bone o ma ion, howe e ; inc easing e idence poin o i s in e e ence
wi h he p ope unc ion o nea ly e e y issue in ou bodies including b ain, hea , muscles, immune sys em and
skin. The eby i s de iciency has been inc imina ed in a long panel o diseases including cance s, au oimmune
diseases, ca dio ascula and neu ological diso de s. I s in ol emen in he pa hogenesis o di e en de ma ologi-
cal diseases is no excep ion and has been he subjec o much esea ch o e he ecen yea s. In he cu en e iew,
we will h ow ligh on his highly dispu ed i amin ha is c ea ing a signi ican conce n om a de ma ological
pe spec i e. Fu he mo e, he consequences o i s de iciency on he skin will be in ocus.
Keywo ds: Vi amin D, De iciency, De ma ology, Immunological
In oduc ion
I is somewha i onic ha i amin D, h ough a his-
o ical acciden , became classi ied as a ‘ i amin’, ow-
ing o he ac ha i amin is con en ionally de ined as
‘essen ial i em needed in he die ’. The pa adox wi h
‘ i amin D’ is ha die pe se is usually poo in i amin
D excep o cod o o he ish oils o ood o i ied wi h
his i amin [1].
Vi amin D is ac ually a a -soluble p oho mone
s e oid ha has endoc ine, pa ac ine and au oc ine
unc ions [2]. The endoc ine e ec s o i amin D a e
mainly in ol ed in se um calcium homeos asis. Vi a-
min D and calcium a e o en used in he same sen ence
because hey wo k closely oge he , i amin D’s p i-
ma y ole is o con ol he le els o calcium ound in
he bloods eam by cons an ly allowing calcium and
phospha e abso p ion om he in es ine o aking cal-
cium om bones. Fu he mo e, i amin D is an ena-
bling agen ha , when p esen in op imal concen a-
ions, has no pe cep ible e ec on calcium abso p ion
in i s own igh ; howe e , i pe mi s o acili a es lexi-
ble physiologic esponse o a ying calcium need [3].
The pa ac ine and au oc ine e ec s o i amin D
depend on gene ic ansc ip ion, unique o he ype o
cell exp essing nuclea i amin D ecep o s. These po-
en ial e ec s include inhibi ion o cell p oli e a ion,
p omo ion o cell di e en ia ion, and apop osis which
may in u n ha e oles in cance , immuni y, and many
o gan sys ems (4-8). The po en ial my iad e ec s o
his i amin in human heal h and disease ha e led o an
escala ing in e es in i amin D inadequacy and he bes
me hods o no malize subop imal le els.
Sunligh
The mos well-known sou ce o i amin D is ia
syn hesis in he skin induced by sun exposu e. The i s
e e ence o he physiological e ec o sunligh on i -
amin D was illus a ed by he G eek his o ian He odo-
us. He isi ed he ba le ield whe e Cambyses (525
BC) o e came he Egyp ians, and inspec ed he skulls
o slain Pe sians and Egyp ians. He no ed ha he Pe -
sian skulls we e so agile ha hey b oke e en when
s uck wi h a pebble, whe eas hose o he Egyp ians
we e s ong and could sca cely be b oken e en when
s uck wi h a s one. The Egyp ians’ explana ion o He-
odo us was ha hey wen ba eheaded om childhood
exposing hei heads o sunligh , whe eas Pe sians co -
e ed hei heads wi h u bans shading hem om he sun
esul ing in skull bone weakness. La e on, in he mid
17 h cen u y F ancis Glisson, P o esso o Physics a
Camb idge Uni e si y, in his ea ise on icke s ob-
se ed ha he disease was common among in an s and
young child en o coun y a me s who a e well, and
whose die s we e known o include eggs and bu e ,
bu who li ed in ainy, mis y pa s o he coun y and
who we e kep indoo s du ing long se e e win e s (11).
Vi amin D syn hesis in he skin
Acco ding o he Commission In e na ionale de
l’Eclai age (CIE) (12), he i amin D e ec i e adia ion
is desc ibed in e ms o i s ac ion spec um (i.e., he e -
iciency o each wa eleng h o syn hesize i amin D in
skin) which co e s he spec al ange (255–330 nm)
wi h a maximum a abou 295 nm (UVB). A whole
body exposu e o UVB adia ion inducing he ligh pink
colo o he minimal e y hema dose o 15–20 min is
able o induce he p oduc ion o up o 250 μg i amin
D (10,000 IU) [13], [14].
No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025 51
I s p ecu so 7-dehyd ocholes e ol in he plasma
memb anes o bo h epide mal basal and sup abasal
ke a inocy es and de mal ib oblas s is con e ed o
p e i amin D3. Cu aneously syn hesized i amin D3 is
eleased om he plasma memb ane and en e s he sys-
emic ci cula ion bound o i amin D-binding p o ein
(DBP) (15). Se um concen a ions o i amin D3 peak
24–48 h ollowing exposu e o UV adia ion (13).
The ea e , i amin D3le els decline exponen ially
wi h a se um hal -li e anging om 36 o 78 h (13,14).
As a lipid-soluble molecule, i amin D3 can be aken
up by adipocy es and s o ed in subcu aneous o omen al
a o la e use (16). The dis ibu ion o i amin
D3 in o adipose issue p olongs i s o al-body hal -li e
o app oxima ely wo mon hs as i s de ec ed on expe -
imen s on subma ine pe sonnel (17-19).
Once in he ci cula ion, i amin D is con e ed by
a hepa ic hyd oxylase in o 25-hyd oxy i amin D
(25(OH)D; calcidiol). The ci cula ing 25(OH)D le el is
an indica o o he i amin D s a us. This le el e lec s
bo h ul a iole exposu e and die a y i amin D in ake.
The se um hal -li e o 25(OH)D is app oxima ely
15 days (2). 25(OH)D is no biologically ac i e excep
a e y high, non-physiological le els (20). As needed,
25(OH)D is con e ed in he kidney o i s ac i e ho -
monal o m 1,25-dihyd oxy i amin D (1,25(OH)2D;
calci iol) in a p ocess which is usually igh ly con-
olled by he pa a hy oid ho mone which le els s a
ising a 25(OH)D cu o le els o 75 nmol/L o lowe .
In spi e o his, inadequa e i amin D supply lowe s he
ci cula ing le el o calci iol (16). Ci cula ing calci iol
is also ad e sely a ec ed by a educed numbe o ia-
ble neph ons, high se um concen a ions o ib oblas
g ow h ac o -23, and high le els o in lamma o y cy-
okines such as in e leukin (IL)-1, IL-6, and umo ne-
c osis ac o -alpha (TNF-α) (19, 21).
I is impo an o know ha he con e sion o p e-
i amin D3 o he inac i e pho op oduc s lumis e ol
and achys e ol balances he cu aneous biosyn hesis o
i amin D3 as a eedback loop. This mechanism en-
su es ha one canno “o e dose” on i amin D3 by
pho oexposu e alone. A e less han 1 minimal e y-
hema dose (MED; i.e., he amoun o pho oexposu e
equi ed o p oduce ain pinkness in he skin a 24 h
a e exposu e), he concen a ion o p e i amin
D3 eaches maximal le els and u he UV adia ion
me ely esul s in he p oduc ion o inac i e me abo-
li es (2).
Die a y sou ces and supplemen s
Vi amin D is a ailable in 2 dis inc o ms, e gocal-
ci e ol ( i amin D2) and cholecalci e ol ( i amin D3).
Sunshine exposu e p o ides i amin D in he o m o
D3 only, while die a y sou ces a e able o p o ide bo h
o ms, which a e o icially ega ded by many as equi -
alen and in e changeable (22-24). Howe e , se e al
easons ha e been sugges ed o a gue agains his p e-
sump ion including ha bo h a e di e en in hei e i-
cacy a aising se um 25-hyd oxy i amin D, wi h di-
minished binding o i amin D2 me aboli es o i amin
D binding p o ein in plasma, as well as he de ec ion o
a nonphysiologic me abolism and sho e shel li e o
i amin D2. Ne e heless, s ill o his day, he majo
p epa a ions o i amin D o p esc ip ion a e in he
o m o i amin D2, no i amin D3. Mul i i amins may
con ain ei he i amin D2 o i amin D3, bu mos com-
panies a e now e o mula ing hei p oduc s o con ain
i amin D in he D3 o m (25).
The e a e only ew na u al sou ces o i amin D
including cod li e oil, cheese, egg yolks, macke el,
salmon, una ish, and bee li e . Because i is no easy
o many indi iduals o ob ain adequa e i amin D in-
ake om na u al die a y sou ces alone, many coun ies
o i y oods such as o ange juice, milk, yogu , and ce-
eal wi h i amin D. Many inexpensi e supplemen al
i amin D o ms a e eadily a ailable o e he coun e
in bo h i amin D3 and i amin D2 o ms and wi h o
wi hou calcium (26, 27).
Vi amin D le els
Di e en cu -o alues o he no mal h eshold
o i amin D ha e been used un il ecen ly (28). A le el
o 50 nmol/L has been widely used o de ine 25(OH)D
insu iciency, while some s udies ha e used
37.5 nmol/L as he lowes le el o su iciency (29-31).
Fu he s udies, howe e , sugges ha a 25-(OH)D
le el as high as 75 nmol/L o highe is needed o co e
all physiological unc ions o i amin D and should
he e o e be conside ed op imal (32-36).
Fac o s in luencing i amin D le el
Nu ien de iciencies a e usually he esul o die-
a y inadequacy, impai ed abso p ion and use, in-
c eased equi emen , o inc eased exc e ion. Vi amin D
de iciency can occu when usual in ake is lowe han
ecommended le els o e ime, exposu e o sunligh is
limi ed, he kidneys canno con e 25(OH)D o i s ac-
i e o m, o abso p ion o i amin D om he diges i e
ac is inadequa e. Vi amin D-de icien die s a e asso-
cia ed wi h milk alle gy, lac ose in ole ance, o o- ege-
a ianism, and eganism (37).
Rega ding he amoun o i amin D p oduc ion in
human skin, i depends on se e al a iables including
en i onmen al ac o s such as geog aphic la i ude, sea-
son, ime o day, wea he condi ions (cloudiness),
amoun o ai pollu ion and su ace e lec ion which
can all in e e e wi h he amoun o UVB adia ion
eaching he skin (38-41).
Pe sonal a ia ions ep esen ano he g oup o in-
luen ial ac o s a ec ing he i amin D p oduc ion in
he skin, including age as elde ly people ha e hinne
skin, and consequen ly a e less capable o syn hesizing
i amin D (7, 38, 39) and obesi y as o e weigh indi-
iduals ha e educed i amin D le els (42). I is also
no ewo hy ha skin ypede e mines a pe son’s e ec-
i eness in p oducing i amin D. Ligh skins ( ype I)
p oduce up o six old he amoun o i amin D p o-
duced by da k skins ( ype VI). In addi ion, clo hing
habi s, li es yle, wo kplace (e.g., indoo e sus ou -
doo ), and sun a oidance p ac ices ha e a s ong im-
pac on i amin D syn hesis (38-41)
The in luence o some common p ac ices as us-
ing sunblocks o ecei ing sunbeds on i amin D p o-
duc ion is ano he poin o in e es . Sunblocks a e
known o block UVB adia ion e ec i ely. Howe e , i
is ques ionable whe he sunsc een in p ac ice causes
any i amin D de iciency. Absolu e ull-body co e age
o sunsc een is uncommon. Some a eas o he skin a e
always le ou . A imes and loca ions whe e he sun is
52 No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025
in ense and he empe a u e is high enough o make he
popula ion use sunsc een, i s i amin D s a us is gene -
ally e y sa is ac o y (39-41). On he o he hand he use
o sun beds is con o e sial, bu ega dless, subjec s
who egula ly use anning beds ha emi UVB adia ion
a e likely o ha e highe 25(OH)D concen a ions. Ne -
e heless, he e is a end owa d discou aging he use
o such anning beds o ea o melanoma and non-
melanoma skin cance (43).
Vi amin D: Wha ’s beyond i s syn hesis and
me abolism?
The skin is unique in being no only he sou ce o
i amin D o he body bu also in being capable o e-
sponding o he ac i e me aboli e o i amin D,
1,25(OH)2D. Bo h 1,25(OH)2D and i s ecep o (VDR)
play essen ial oles in he skin.
Skin di e en ia ion and p oli e a ion
Bo h calcium and 1,25(OH)2D pe o m impo an
and in e ac ing unc ions in egula ing he skin di e -
en ia ion p ocess. 1,25(OH)2D inc eases he exp ession
o in oluc in, ansglu aminase, lo ic in, and ilagg in
and inc eases ke a inocy e co ni ied en elope o -
ma ion while inhibi ing p oli e a ion (44, 45). These
ac ions a e due o, a leas in pa , he abili y o
1,25(OH)2D o inc ease in acellula calcium le els
achie ed by induc ion o he calcium ecep o (46), and
he phospholipase C (47) ha a e c i ical o he abili y
o calcium o s imula e ke a inocy e di e en ia ion (48,
49). Mice lacking he VDR show de ec i e epide mal
di e en ia ion mani es ing as educed le els o in olu-
c in and lo ic in and loss o ke a ohyaline g anules (50,
51). Cu aneous an imic obial e ec s
1,25(OH)2D and i s ecep o egula e he p o-
cessing o he long chain glycosylce amides ha a e
c i ical o he skin ba ie o ma ion (52) which is c u-
cial in de ending he skin. Fu he mo e, hey induce oll
like ecep o 2 (TLR2) and i s co ecep o CD14, ha
ini ia e he inna e immune esponse in skin (53). Ac i-
a ion o hese ecep o s leads o he induc ion o
CYP27B1, which in u n induces ca helicidin esul ing
in he killing o in asi e o ganisms (53, 54). Mice lack-
ing he VDR o he enzyme (CYP27B1) show de-
c eased lipid con en o he lamella bodies leading o a
de ec i e pe meabili y ba ie (52), and a de ec i e e-
sponse o he inna e immune sys em o in ading in ec-
ions (53).
Vi amin D and cu aneous inna e immuni y
The his o ical link be ween i amin D and inna e
immune unc ion s emmed ini ially om he use o cod
li e oil as ea men o ube culosis (TB) (54). Mo e
ecen wo k has ocused on he cellula and molecula
machine y ha unde pins he ac ions o i amin D on
he pa hogen ha causes TB, Mycobac e ium ube cu-
losis (M. TB). In he i s o hese s udies, ca ied ou
25 yea s ago, ac i e 1,25(OH)2D was shown o educe
he p oli e a ion o M. TB in mac ophages wi h his e -
ec being enhanced by he cy okine in e e on γ
(IFNγ), a known s imula o o mac ophages (55). How-
e e , he majo ad ance in ou unde s anding o how
i amin D di ec s an ibac e ial esponses in TB a ose
om much mo e ecen s udies aiming a de ining he
way by which monocy es and mac ophages, key cells
in di ec ing bac e ial killing, espond o an encoun e
wi h M. TB (56). These da a sugges ed ha monocy es
p omo e localized ac i a ion o i amin D in esponse
o M. TB, wi h he esul ing 1,25(OH)2D binding o en-
dogenous VDR. In his way, i amin D can ac o mod-
ula e gene exp ession in esponse o M. TB immune
challenge – a classical in ac ine mechanism (57, 58).
Func ional analyses showed ha 25OHD-media ed in-
duc ion o ca helicidin is coinciden wi h enhanced kill-
ing o M. TB in monocy es. Na u ally occu ing a ia-
ions in se um 25OHD ha e been shown o co ela e
wi h induc ion o monocy e ca helicidin exp es-
sion (59). The conclusion om hese s udies was ha
indi iduals wi h low se um 25OHD will be less able o
suppo monocy e induc ion o an ibac e ial ac i i y
and may he e o e be a g ea e isk o in ec ion. Con-
e sely, supplemen a ion o i amin D-insu icien in-
di iduals in i o has been shown o imp o e TLR-
media ed induc ion o monocy e ca helicidin (60) and
may he e o e help o p o ec agains in ec ion.
S udies ha e shown ha T-cell cy okines play a
pi o al ole in bo h ampli ying and a enua ing i amin
D-media ed ca helicidin p oduc ion (61). Indeed, cy o-
kine p oduc ion by monocy es hemsel es may be cen-
al o he in ac ine me abolism o i amin D in his
cell ype (62, 63). Thus, i seems likely ha he abili y
o moun an app op ia e esponse o in ec ion will be
highly dependen on he a ailabili y o i amin D, wi h
addi ional uning o his esponse by o he componen s
o he no mal human immune esponse.
Vi amin D can also in luence inna e immune e-
sponses o pa hogens ia e ec s on an igen p esen a-
ion by mac ophages o dend i ic cells. These cells a e
known o exp ess VDR (64), and ea men wi h
1,25(OH)2D has been shown o inhibi DC ma u a ion,
supp ess an igen p esen a ion and p omo e a ole o-
genic T-cell esponse (65, 66).
Vi amin D and cu aneous adap i e immuni y
Ea ly s udies o i amin D and he immune sys em
demons a ed VDR exp ession in bo h T and B
cells (67). No ably, VDR exp ession by hese cells was
only immunologically unc ional in ac i e, p oli e a -
ing cells, sugges ing an an ip oli e a i e ole o
1,25(OH)2D on hese cells (68). T helpe (Th) cells ap-
pea o be he p incipal a ge o 1,25(OH)2D which
can supp ess Th cell p oli e a ion as well as modula ing
cy okines p oduc ion by hese cells (69). Ac i a ion o
nai e Th cells by an igen in u n leads o he gene a ion
o Th cell subg oups wi h dis inc cy okine p o iles:
Th1 (IL-2, IFN γ, umo nec osis ac o alpha) and Th2
(IL-3, IL-4, IL-5, IL-10) ha espec i ely suppo cell-
media ed and humo al immuni y (70-71).
In i o 1,25(OH)2D inhibi s Th1 cy okines (72),
while p omo ing Th2 cy okines (73). A hi d g oup o
Th cells known o be in luenced by i amin D a e in e -
leukin-17 (IL-17)-sec e ing T cells (Th17 cells). Au o-
immune disease-suscep ible non obese diabe ic (NOD)
mice ea ed wi h 1,25D exhibi lowe le els o IL-
17 (74), and 1,25(OH)2D-media ed supp ession o mu-
ine e inal au oimmuni y appea s o in ol e inhibi ion
o Th17 ac i i y (75). Fu he mo e, subsequen s udies
No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025 53
ha e shown ha 1,25(OH)2D supp esses IL-17 p oduc-
ion ia di ec ansc ip ional supp ession o IL-17 gene
exp ession (76).
Ano he g oup o T cells known o be po en ly in-
duced by 1,25(OH)2D a e egula o y T cells
(T egs) (77). Al hough pa o he Th cell amily, T egs
ac o supp ess immune esponses by o he T cells as
pa o he machine y o p e en o e -exube an o au-
oimmune esponses (78). Recen s udies ha e unde -
lined he impo ance o T egs in media ing he immu-
no egula o y ac ions o i amin D. Adminis a ion o
1,25(OH)2D sys emically o pa ien s who unde wen
enal ansplan a ion has been shown o expand ci cu-
la ing T eg popula ions (79).
S udies o i amin D and T-cell unc ion ha e o
da e ocused p ima ily on he esponse o hese cells o
ac i e 1,25(OH)2D. Wha is less clea is he mechanism
by which a ia ions in i amin D s a us can also in lu-
ence T cells, despi e epo s linking se um le els o
25OHD wi h speci ic T-cell popula ions (56). Fo ex-
ample, ci cula ing le els o 25OHD ha e been shown
o co ela e wi h T egs ac i i y in pa ien s wi h mul iple
scle osis (80, 81). The e a e ou po en ial mechanisms
by which se um 25OHD is belie ed o in luence T-cell
unc ion; (i) di ec e ec s on T cells media ed ia sys-
emic 1,25(OH)2D; (ii) indi ec e ec s on an igen
p esen a ion o T cells media ed ia localized DC ex-
p ession o CYP27B1 and in ac ine syn hesis o
1,25(OH)2D; (iii) di ec e ec s o 1,25(OH)2D on T
cells ollowing syn hesis o he ac i e o m o i amin
D by CYP27B1-exp essing monocy es o DCs – a pa a-
c ine mechanism; (i ) In ac ine con e sion o 25OHD
o 1,25(OH)2D by T cells. As ye , i is unclea whe he
one o mo e o hese mechanisms will apply o he eg-
ula ion o speci ic T-cell ypes. Fo example, he e ec s
o 1,25(OH)2D on T egs can occu indi ec ly ia e -
ec s on DCs (82), bu may also in ol e di ec e ec s
on he T egs (83). Howe e , as DCs also exp ess
CYP27B1 (84) and may he e o e ac as he condui o
25OHD e ec s on T egs. In e es ingly, epo s ha e
also desc ibed exp ession o CYP27B1 by T cells (85),
sugges ing ha 25OHD may also in luence he unc ion
o hese cells ia an in ac ine mechanism, al hough he
p ecise ele ance o his o speci ic T-cell ypes e-
mains unclea (56).
Despi e he ac ha exp ession o VDR by B cells
has been ecognized o many yea s (67), he abili y o
1,25(OH)2D o supp ess B-cell p oli e a ion and im-
munoglobulin (Ig) p oduc ion was ini ially conside ed
o be an indi ec e ec media ed ia Th cells (68). How-
e e , mo e ecen s udies ha e con i med di ec e ec s
o 1,25(OH)2D on B-cell homoeos asis (86), wi h no a-
ble e ec s including inhibi ion o plasma cells and class
swi ched memo y cells di e en ia ion. These e ec s
lend u he suppo o i amin D’s p oposed ole in B-
cell- ela ed au oimmune diso de s such as sys emic lu-
pus e y hema osis. O he B-cell a ge s known o be
modula ed by o 1,25(OH)2D include IL-10 (87) and
CCR10 (88), sugges ing ha he epe oi e o B-cell e-
sponses o i amin D ex ends beyond i s e ec s on B-
cell p oli e a ion and Ig syn hesis (56).
Hai ollicle cycling
In i o s udies ha e suppo ed he concep ha
VDR may play a i al ole in he pos na al main enance
o he hai ollicle. Mesode mal papilla cells and he
ou e oo shea h (ORS) epide mal ke a inocy es ex-
p ess VDR in a ied deg ees in co ela ion wi h he
s ages o he hai cycle. In bo h he la e anagen and ca -
agen s ages he e is an inc ease in VDR, which is asso-
cia ed wi h dec eased p oli e a ion and inc eased di -
e en ia ion o he ke a inocy es. These changes a e
hough o p omo e he p og ession o he hai cy-
cle (89).
Limi ed s udies ha e been done in humans o elab-
o a e he ole o i amin D in he hai cycle. A po en ial
applica ion o i amin D is in chemo he apy-induced
alopecia. Topical calci iol has been shown o p o ec
agains chemo he apy-induced alopecia caused by
pacli axel and cyclophosphamide. Howe e , opical
calci iol ailed o p o ec agains chemo he apy-in-
duced alopecia caused by a combina ion o 5- luo ou a-
cil, doxo ubicin, and cyclophosphamide and a combi-
na ion o cyclophosphamide, me ho exa e, and 5-
luo ou acil. The abili y o opical calci iol o p e en
chemo he apy-induced alopecia may he e o e depend
on he chemo he apy agen s used. O no e, he s udies
in which no e ec s we e obse ed, we e small and may
ha e used doses o i amin D ha we e inadequa e o
p o ec agains chemo he apy-induced alopecia (90).
The sebaceous gland
I has been epo ed ha incuba ion o he human
sebaceous gland cell line wi h 1,25OH2D esul s in a
dose-dependen supp ession o cell p oli e a ion. Using
eal- ime PCR, i was demons a ed ha key compo-
nen s o he i amin D sys em (VDR, 25OHase, 1αO-
Hase, and 24OHase) a e s ongly exp essed in such
cells. I has been concluded ha local syn hesis o me-
abolism o i amin D me aboli es may be o im-
po ance o g ow h egula ion and a ious o he cellu-
la unc ions in sebaceous glands and ha sebaceous
glands ep esen p omising a ge s o he apy wi h i -
amin D analogs o o pha macological modula ion o
calci iol syn hesis/me abolism (91, 92).
Pho op o ec ion
Pho odamage e e s o skin damage induced by ul-
a iole (UV) ligh . Depending on he dose, UV ligh
can lead o DNA damage, in lamma o y esponses,
skin cell apop osis (p og ammed cell dea h), skin ag-
ing, and skin cance . Some s udies, mainly in i o (cell
cul u e) s udies (93-96) and mouse s udies whe e 1,25-
dihyd oxy i amin D3 was opically applied o skin be-
o e o immedia ely ollowing i adia ion (93, 97, 98),
ha e ound ha i amin D exhibi s pho op o ec i e e -
ec s. Documen ed e ec s on skin cells include de-
c eased DNA damage, educed apop osis, inc eased
cell su i al, and dec eased e y hema. The mechanisms
o such e ec s a e no known, bu one mouse s udy
ound ha 1,25-dihyd oxy i amin D3 induced exp es-
sion o me allo hionein (a p o ein ha p o ec s
agains ee adicals and oxida i e damage) in he s a-
um basale (93). I has also been pos ula ed ha non-
genomic ac ions o i amin D con ibu e o he pho o-
p o ec ion (99); such e ec s o i amin D in ol e cell-
signaling cascades ha open calcium channels (100).
54 No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025
Wound healing
1,25-Dihyd oxy i amin D3 egula es he exp es-
sion o ca helicidin (LL-37/hCAP18) (53, 57), an an i-
mic obial p o ein ha appea s o media e inna e im-
muni y in skin by p omo ing wound healing and issue
epai . One human s udy ound ha ca helicidin exp es-
sion is up egula ed du ing ea ly s ages o no mal
wound healing (58). O he s udies ha e shown ha
ca helicidin modula es in lamma ion in skin (101), in-
duces angiogenesis (102), and imp o es eepi heliali-
za ion ( he p ocess o es o ing he epide mal ba ie o
e-es ablish a unc ional ba ie ha p o ec s unde lying
cells om en i onmen al exposu es) (103). The ac i e
o m o i amin D and i s analogs ha e been shown o
up egula e ca helicidin exp ession in cul u ed ke a ino-
cy es (58, 104). Howe e , mo e esea ch is needed o
de e mine he ole o i amin D in wound healing and
epide mal ba ie unc ion, and whe he o al i amin D
supplemen a ion o opical ea men wi h i amin D
analogs is help ul in healing su gical wounds.
Vi amin D and skin diseases
Based on he a o e men ioned ac s conce ning he
in e wined bonding ha exis s be ween i amin D and
skin, i seems only “na u al” o inc imina e i amin D
de iciency in a long lis o cu aneous diso de s includ-
ing skin cance , pso iasis, ich hyosis, au oimmune skin
diso de s such as i iligo, blis e ing diso de s, scle o-
de ma and sys emic lupus e y hema osus, as well as
a opic de ma i is, acne, hai loss, in ec ions and pho o-
de ma oses. Ne e heless, i emains specula i e
whe he i amin D de iciency p ima ily con ibu es o
disease pa hogenesis o me ely ep esen s a consequen-
ial e en o he in lamma o y p ocesses in ol ed. Ac-
co ding o a ecen sys ema ic e iew including 290
p ospec i e coho s udies and 172 andomized ials o
majo heal h ou comes and o physiological pa ame e s
ela ed o disease isk o in lamma o y s a us, one solid
ac is emphasized; i amin D de iciency appea s o be
a ma ke o ill heal h (105) ega dless o being an ac-
ual cause o an associa ion. In he cu en e iew we
will highligh he mos commonly s udied de ma olog-
ical diseases.
Skin cance
A numbe o epidemiologic s udies ha e sug-
ges ed ha i amin D may ha e a p o ec i e e ec de-
c easing cance isk and cance -associa ed mo al-
i y (106-110). Adequa e i amin D s a us has been
linked o dec eased isks o de eloping speci ic can-
ce s, including cance s o he esophagus, s omach, co-
lon, ec um, gallbladde , panc eas, lung, b eas , u e us,
o a y, p os a e, u ina y bladde , kidney, skin, hy oid,
and hema opoie ic sys em (e.g., Hodgkin’s lymphoma,
non-Hodgkin’s lymphoma, mul iple myeloma) (110).
Wi h ega ds o skin cance , epidemiologic and labo a-
o y s udies ha e epo ed mixed indings, wi h some
epo ing an associa ion be ween highe i amin D le -
els and inc eased skin cance isk (111), o he s showing
a dec eased skin cance isk (106-109), and s ill o he s
showing no associa ion (106). The key indings ha
poin o he ole o i amin D in he p e en ion o he
ini ia ion and p og ession o le hal skin cance s a e he
in ol emen o i amin D in egula ion o mul iple sig-
naling pa hways ha ha e implica ions in ca cinogene-
sis (109), among which a e he inhibi ion o he hedge-
hog signaling pa hway, he pa hway unde lying de el-
opmen o basal cell ca cinomas, and up egula ion o
nucleo ide excision epai enzymes (106). Fu he -
mo e, i amin D induces cellula a es , igge s apop-
o ic pa hways, inhibi s angiogenesis, and al e s cellula
adhesion (108). Ano he poin is ha skin cance me-
as asis depends on he umo mic oen i onmen ,
whe e i amin D me aboli es play a key ole in p e en-
ion o ce ain molecula e en s in ol ed in umo p o-
g ession (109). The key ac o complica ing he associ-
a ion be ween i amin D and skin cance is ul a iole
B adia ion. The same spec um o ul a iole B adia-
ion ha ca alyzes he p oduc ion o i amin D in he
skin also causes DNA damage ha can lead o epide -
mal malignancies. O e all, he e is some e idence ha
i amin D may play a ole in nonmelanoma skin cance
(NMSC) including basal cell and squamous cell ca ci-
noma as well as melanoma p e en ion, al hough as o
ye he e is no di ec e idence o show a p o ec i e e -
ec (106).
Pso iasis
Pso iasis is a ch onic in lamma o y skin disease
ha a ec s 2–3% o he popula ion wo ldwide and
causes signi ican mo bidi y (112). Al hough he pa h-
ogenesis o pso iasis is no ully unde s ood, he e is
ample e idence sugges ing ha he dys egula ion o he
immune cells in he skin, pa icula ly T cells, plays a
c i ical ole in pso iasis de elopmen (113).
Se e al s udies ha e ocused on he possible ole
o i amin D de iciency in pso iasis (114-116). The ex-
ac mechanism by which i amin D de iciency con ib-
u es in such a complex pa hogenesis is no ully unde -
s ood. Se e al pa hways ha e been es ablished includ-
ing, loss o he an i-p oli e a i e unc ion o i amin D,
as i has been ound ha human cul u ed ke a inocy es
exposed o calci iol showed ma ked inhibi ion o
g ow h and accele a ed ma u a ion (117). Mo eo e , as
in lamma ion and angiogenesis ep esen co ne s ones
in he pa hogenesis o pso iasis (118, 119), he loss o
he an i-in lamma o y and an i-angiogenic ac i i y o
i amin D (108) could ep esen ano he explana ion o
he con ibu ion o he i amin D de iciency in pso ia-
sis. As 1α,25-dihyd oxy i amin D3 is known o sup-
p ess he Th1 and Th17 cell p oli e a ion (69), as well
as induce he T egs (120), ano he p oposed pa hway
h ough which i amin D de iciency could sha e in he
pso ia ic p edicamen would be he unchecked p oli e -
a ion o Th1 and 17 cells on one hand and unchecked
inhibi ion o T egs on he o he hand. Topical ea men
wi h calcipo iol has been shown o signi ican ly de-
c ease cu aneous le els o human be a de ensins (HBD)
2 and HBD3 as well as IL-17A, IL-17F and IL-8, which
play signi ican oles in pso iasis (121), u he linking
i amin D de iciency o he pa hogenesis o pso iasis.
Owing o his pos ula ed ole played by i amin D
in he pa hogenesis o pso iasis, i is no wonde ha i
is one o he mos popula ly p esc ibed opical medica-
ions o his disease, singly o in combina ion wi h be-
ame hasone, and nume ous s udies documen ed he e -
icacy and sa e y o using opical calcipo iol in he
No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025 55
ea men o cases o localized plaque pso iasis (122-
126).
Acne and osacea
Acne ulga is is he mos common skin diso de
a ec ing millions o people wo ldwide. In lamma ion
esul ing om he immune esponse a ge ing P opion-
ibac e ium acnes (P. acnes) has a signi ican ole in
acne pa hogenesis. In a ecen s udy, i has been demon-
s a ed ha P. acnes is a po en induce o Th17, and
ha 1,25OH2D inhibi s P. acnes-induced Th17 di e -
en ia ion, and he eby could be conside ed as an e ec-
i e ool in modula ing acne (127). Fu he mo e, sebo-
cy es we e iden i ied as 1,25OH2D esponsi e a ge
cells, indica ing ha i amin D analogs may be e ec-
i e in he ea men o acne. In ano he ecen s udy,
he exp ession o in lamma o y bioma ke s ha e been
shown o be in luenced by ea men wi h i amin D in
cul u ed sebocy es, bu no h ough VDR (128).
In he same spec um o acne, ano he s udy
demons a ed ela i ely high se um le els o i amin D
in pa ien s wi h osacea which is a common ch onic
skin condi ion a ec ing he ace, in compa ison wi h
con ols, sugges ing ha inc eased i amin D le els
may lead o he de elopmen o osacea (129).
Hai loss
The ole o i amin D in hai migh be explained
by he ac ha an op imal concen a ion o i amin D
has been sugges ed o be necessa y o delay he aging
phenomena, including hai loss (130). Recen ly i has
been shown ha 1,25OH2D/VDR p omo es he abili y
o β-ca enin o s imula e hai ollicle di e en ia-
ion (131). Mo eo e ex ensi e da a om animal mod-
els clea ly show ha he VDR ac i a ion plays an im-
po an ole in he hai ollicle cycle, speci ically
anagen ini ia ion (132). In e es ingly, in VDR abla ed
mice i did no seem ha no maliza ion o mine al ion
homeos asis by a die high in calcium and phospho ous
p e en ed alopecia sugges ing ha he mechanism o
alopecia is un ela ed o mine al le els bu a he o he
i amin D le els (133). Fu he mo e, ecen da a sug-
ges ed ha VDR egula es di ec ly o indi ec ly he ex-
p ession o genes equi ed o hai ollicle cycling, in-
cluding he hedgehog signaling pa hway (134).
A ecen s udy conduc ed on eigh y emale pa-
ien s demons a ed ha low se um i amin D2 is asso-
cia ed wi h bo h common ypes o hai loss in emales
namely; elogen e lu ium and and ogene ic emale
pa e n hai loss. I was sugges ed ha sc eening o i -
amin D le el and supplemen a ion wi h i amin D in
cases wi h de iciency would be bene icial in he man-
agemen o hese condi ions (135).
In con adis inc ion o he p oposal o he im-
po an ole played by i amin D in hai loss, a placebo-
con olled ial on 26 pa ien s showed ha calcipo iol
did no a ec he elogen o anagen a io a e 6 weeks
o ea men in pa ien s wi h scalp pso iasis. I is o be
no ed ha he op imal e ec o calcipo iol on pso iasis
was no seen un il 8 weeks, hus, ollow up migh ha e
been oo b ie o de ec an e ec o calcipo iol on hai
loss (136). Fu he mo e, a c oss sec ional s udy o 296
heal hy men was done o explo e a possible associa ion
be ween male pa e n baldness and se um 25-hy-
d oxy i amin D le els. The se e i y and ex en o he
baldness did no appea o be associa ed wi h se um 25-
hyd oxy i amin D le els (130). This aises he specu-
la ion abou he eal alue o i amin D le els in hai
loss, and whe he he s o y could be in insic, closely
ela ed o he ecep o i sel a he han o he le el o
i amin D.
Vi iligo
Vi iligo is a common pigmen a y diso de cha ac-
e ized by well-dema ca ed depigmen ed pa ches o
macules o di e en shapes and sizes and is caused by
he des uc ion o unc ional melanocy es in he epide -
mis (137).
Vi amin D p o ec s he epide mal melanin uni and
es o es melanocy e in eg i y ia se e al mechanisms
including con olling he ac i a ion, p oli e a ion, mi-
g a ion o melanocy es and pigmen a ion pa hways by
modula ing T cell ac i a ion, which is appa en ly co -
ela ed wi h melanocy e disappea ance in i iligo. The
mechanism h ough which i amin D exe s i s e ec s
on melanocy es is no ye ully unde s ood. Vi amin D
is belie ed o be in ol ed in melanocy e physiology by
coo dina ing melanogenic cy okines [mos likely endo-
helin-3 (ET-3)] and he ac i i y o he SCF/c-Ki sys-
em, which is one o he mos impo an egula o s o
melanocy e iabili y and ma u a ion (138). Fu he -
mo e, a p oposed mechanism in ol ing i amin D in
he p o ec ion o i iliginous skin is based on i s an i-
oxidan p ope ies and egula o y unc ion owa d he
eac i e oxygen species ha a e p oduced in excess in
i iligo epide mis (139). Ano he poin is ha he ac i e
o m o i amin D educes he apop o ic ac i i y in-
duced by UVB in ke a inocy es and melanocy es (140),
ha has been epo ed o emo e melanocy es om he
skin (141). Mo eo e , i amin D migh exe immuno-
modula o y e ec s by inhibi ing he exp ession o IL-
6, IL-8, TNF-α, and TNF-γ, modula e dend i ic cell
ma u a ion, di e en ia ion, and ac i a ion as well as in-
duce he inhibi ion o an igen p esen a ion [65], he eby
dampen he au oimmune pa hway inc imina ed in he
pa hogenesis o i iligo.
I is s ill unknown i i amin D de iciency plays a
ole in causing i iligo, as i does in o he au oimmune
diseases. In 2010 Sil e be g and Sil e be g (142) as-
sessed se um 25-hyd oxy i amin D (25(OH)D) le els
in 45 pa ien s wi h i iligo and i appea ed ha 55.6%
we e insu icien (22.5–75 nmol/L) and 13.3% we e
e y low (<.22.5 nmo/L) a inding ha was e-demon-
s a ed by o he s (143). Howe e , ano he s udy
showed no co ela ion be ween 25(OH)D and i i-
ligo (144).
Rega dless he exis ing con o e sy, opical i a-
min D3 analogs a e membe s o he a mamen a ium o
he apeu ic modali ies o i iligo. The use o i amin
D analogs in combina ion wi h PUVAsol and opical
calcipo iol o he ea men o i iligo was i s e-
po ed by Pa sad e al. (145). Subsequen ly, a numbe
o s udies ha e epo ed on he ea men o i iligo
wi h i amin D analogs alone o in combina ion wi h
ul a iole ligh o co icos e oids o enhance epigmen-
a ion (142, 146, 147) wi h some con adic o y e-
sul s (148-150).
56 No wegian Jou nal o de elopmen o he In e na ional Science No 168/2025
Pemphigus ulga is and bullous pemphigoid
Pemphigus ulga is and bullous pemphigoid a e
po en ially a al au oimmune bullous diso de s caused
by ke a inocy e acan holysis as a esul o pa hogenic
an ibody p oduc ion by B cells. Vi amin D, h ough i s
pa icipa ion in se e al immune modula o y unc ions
including B cells apop osis, Th2 cell di e en ia ion,
apop o ic enzyme egula ion and T egs unc ions, may
be ac i ely in ol ed in he immune egula ion o such
diseases. Se e al ecen s udies demons a ed ha pa-
ien s wi h pemphigus ulga is and bullous pemphigoid
ha e signi ican ly lowe se um i amin D le els in
compa ison wi h con ols ega dless age, body mass in-
dex o pa e n o sun exposu e (151, 152). In addi ion,
i was sugges ed ha his lowe le el o i amin D
migh accoun o he inc eased p e alence o ac u es
in such pa ien s and he e o e should be aken in o con-
side a ion in pa ien s who mus be gi en co icos e -
oids (152).
A opic de ma i is
A opic de ma i is (AD) is a common ch onic in-
lamma o y ype o eczema. Se e al s udies ha e
shown ini ial epide mal ba ie dys unc ion wi h subse-
quen immune ac i a ion as he unde lying mechanism.
Animal s udies, case epo s, and andomized clinical
ials ha e sugges ed ha i amin D, h ough a ious
mechanisms including immunomodula ion, may alle i-
a e he symp oms o AD. The majo i y o hese s udies
indica e an in e se ela ionship be ween he se e i y o
a opic de ma i is and i amin D le els. Fu he mo e,
s udies ha e shown ha , in indi iduals wi h AD who
a e de icien in i amin D, eple ion o i amin D e-
sul s in imp o emen and dec eased se e i y o he dis-
ease (153, 154).
Conclusions
In conclusion one could clea ly sense he unique
ela ionship ha en angles i amin D o de ma ology.
On one hand, ou skin is one sou ce o his impo an
i amin and on he o he hand all a ailable da a poin o
i s impo an impac on he heal h o ou skin and he
in ol emen o i s de iciency in he pa hway o many
de ma ological diseases. Se e al ac o s a e esponsible
o main aining i in op imum le els; he e o e sunny
clima es a e by a no a gua an ee o p o iding a
“com o zone” ega ding he possibili y o his i amin
de iciency, a conce n documen ed by se e al epidemi-
ological s udies ca ied ou in a eas close o he equa-
o (155-158). On he basis o cu en ly a ailable da a,
i is clea ha supplemen al i amin D should be he
p e e ed ecommenda ion owa d achie ing i s no mal
se um le els, he eby a oiding he dele e ious e ec s
accompanied by i s de iciency. S ill mo e esea ch is
needed o un a el i s complica ed ies o de ma ological
diseases and c ea e clea guidelines and ecommenda-
ions o i s supplemen a ion.
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