**Background:** Circadian rhythms are approximately 24-hour biological oscillations controlled by molecular clocks present in nearly all mammalian cells. While a hierarchical model originally placed the suprachiasmatic nucleus (SCN) as the master pacemaker, recent evidence shows that peripheral tissues—including skin—can be directly entrained by light, even after SCN ablation. This review consolidates current knowledge on circadian oscillations in skin, their molecular underpinnings, and their intersection with immunity, homeostasis, aging, and seasonal rhythms.
**Methods:** This is a narrative review. The authors synthesized published literature on chronobiology with a focus on skin biology, covering molecular clock architecture, zeitgebers (light, temperature, feeding, glucocorticoids), immune modulation, epidermal homeostasis, seasonal skin changes, and aging-related circadian alterations. No systematic search strategy or inclusion/exclusion criteria are reported.
**Key Results:** The mammalian circadian clock consists of at least three overlapping feedback loops. In the core loop, BMAL1 dimerizes with CLOCK or NPAS2 to drive expression of PER, CRY, ROR, NR1D1, DBP, and other clock-controlled genes via E-box elements. PER and CRY proteins then inhibit their own transcription, generating oscillations. A second loop involves ROR binding to RORE elements to promote BMAL1 and CLOCK transcription, antagonized by NR1D1. A third loop involves DBP and NFIL3 regulating PER via D-box elements. Posttranslational modifications (phosphorylation, glycosylation, ubiquitination, acetylation, SUMOylation) are essential for maintaining oscillatory dynamics. Light is the primary zeitgeber, detected via the optical nerve and transmitted to the SCN, which entrains peripheral clocks via the autonomic nervous system and the hypothalamus-pituitary-adrenal axis (glucocorticoids, catecholamines). Crucially, light can entrain peripheral clocks even after SCN ablation, and photopigment neuropsin (OPN5) expressed in melanocytes and keratinocytes is a proposed mediator, though the source of its cofactor 11-cis retinal in skin remains unknown.
Circadian clock components are integral to immune function. NFIL3 governs development of IFN-γ-producing group 1 innate lymphoid cells and NK cells. ROR-α expression in activated Treg cells attenuates group 2 innate lymphoid cell function, limiting allergic skin inflammation in atopic dermatitis models. Adhesion molecules ICAM-1, VCAM-1, and CD44 vary rhythmically, controlling leukocyte homing. Antimicrobial peptides (Rarres2, Camp, Defb1) show enhanced expression during active phases. The day is partitioned into a heightened vigilance phase (waking hours) and a recovery/repair phase. Inflammation can disrupt circadian clocks via the NF-κB pathway; TNF-α, IFN-γ, IL-1, and LPS can disrupt core clock gene oscillations. In a chronic jet lag mouse model, a single jet lag exposure worsened response to high-dose LPS challenge. In a TLR7-induced psoriasis mouse model, CLOCK and Per2 regulated severity via IL23R modulation. Epidemiological studies associate shift work with higher psoriasis risk.
Epidermal homeostasis follows circadian control. Epidermal stem cells undergo asymmetric division with differentiation occurring in five sequential 24-hour phases (each 4–5 hours). Undifferentiated keratinocytes are primed for differentiation in phase 1 (klf9, notch3 upregulation), calcium-dependent differentiation occurs in phases 2–3 (late night to early morning, with vitamin D metabolism upregulated), and DNA damage protection/stress mediation genes are upregulated in phases 4–5. Differentiated keratinocytes show similar early-phase gene expression but shift to barrier-building genes (differentiation, keratin organization) in later phases. Keratinocyte differentiation increases PER1-2 and DBP oscillation amplitude while decreasing BMAL1 amplitude; overexpression of PER1/2 or decreased CRY1/2 leads to spontaneous oscillations perturbing stem cell division. Daytime wounds heal approximately 60% faster than nighttime wounds. The DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) shows higher activity at night in human skin. In mouse skin, xeroderma pigmentosum group A (XPA) protein exhibits circadian rhythmicity, linking UV exposure timing to skin cancer risk.
Seasonal changes affect skin physiology. Summer challenges include elevated temperature, increased sweat gland activity, elevated TEWL, reduced skin surface pH, and increased UV exposure. Winter challenges include low relative humidity leading to high TEWL, shortened melatonin production duration, and altered barrier function. With aging, the amplitude of clock-controlled gene oscillations decreases in peripheral tissues but not in the SCN (tracked via Per2). Senescent cells show dampened circadian rhythmicity and impaired circadian signal transmission. Aged dermal fibroblasts secrete a unique aging-associated secretory phenotype distinct from canonical SASP, involving inflammatory signaling and tissue microenvironment alteration. Epidermal stem cells maintain robust circadian oscillations under aged conditions but are rewired to adapt to aged-environment stressors.
**Clinical Implications:** Circadian disruption (e.g., shift work) is associated with psoriasis, atopic dermatitis, and impaired skin barrier function. Understanding circadian control of immune responses, stress mediation (NRF2, peroxiredoxins, glutathione peroxidase, sestrins), and DNA repair (OGG1, XPA) could inform chronotherapeutic strategies—timing drug administration to match circadian oscillations of therapeutic targets. Monitoring circadian biomarkers via skin could enable personalized circadian medicine. Resynchronizing peripheral clocks, potentially via skin, may mitigate desynchronization effects. However, the authors note that research on peripheral clock entrainment, interactions, and impact on central SCN function is still in its infancy, and further studies are needed before clinical translation.