The skin, the body’s largest organ (approximately 1.8 m² surface area), serves as a physical barrier against environmental pathogens/insults and a critical regulator of systemic homeostasis through water retention and thermoregulation. Its multilayered architecture and specialized cellular components collectively provide robust defense against microbial invasion, mechanical stress, and chemical exposure (Chambers and Vukmanovic-Stejic, 2020; Nestle et al., 2009). From an anatomical point of view, the skin comprises the following three distinct layers from superficial to deep: epidermis, dermis, and subcutaneous tissue. The epidermis (50–100 μm) consists of the stratum basale, stratum spinosum, stratum granulosum, and outermost stratum corneum. Keratinocytes represent the predominant cell type, constituting over 90% of epidermal cells. Other specialized cell populations include melanocytes, Langerhans cells, dendritic cells, and Merkel cells (Dahabra et al., 2021; Eckhart and Zeeuwen, 2018). Keratinocyte differentiation is initiated by proliferative activity in the stratum basale, followed by progressive migration through epidermal layers. Terminal differentiation culminates during corneocyte formation within the stratum corneum. These organelle-free dead cells establish a formidable physical barrier that effectively prevents pathogen invasion and minimizes transepidermal water loss (Nestle et al., 2009). Melanocytes, residing in the stratum basale, produce pigment-containing melanosomes that determine skin pigmentation and provide photoprotective functions through UV radiation absorption (Rittié and Fisher, 2015).

The dermis (3–5 mm), the principal structural component of the skin, lies beneath the epidermis and interfaces with it through a wavelike dermal–epidermal junction (DEJ) (Lavker et al., 1989). Histologically divided into two regions, the superficial papillary layer consists of loose connective tissues containing extensive vascular networks and sensory nerve endings that facilitate epidermal nourishment and sensory transduction. The deeper reticular layer, comprising dense irregular connective tissues rich in collagen and elastic fibers, constitutes the bulk of the dermis and confers mechanical resilience and elasticity to the skin (Brown and Krishnamurthy, 2024). The metabolically active dermis serves as the primary site for wound healing (Dahabra et al., 2021). Cellular constituents primarily include fibroblasts, macrophages, and other immune cells. Fibroblasts, the principal resident cells, synthesize and maintain collagen/elastic fibers, proteoglycans, and glycosaminoglycans, thereby establishing a 3D ECM network essential for dermal structural integrity (Gerasymchuk et al., 2020; Shin et al., 2019). These cells also play pivotal roles in wound repair and tissue remodeling (Ren et al., 2022). The dermis further harbors numerous skin appendages, including hair follicles, sebaceous glands, and sweat glands (Brown and Krishnamurthy, 2024). Beneath the dermis lies the subcutaneous tissue (hypodermis), which is predominantly composed of adipocytes, bursae, vasculature, and connective tissues. This layer provides thermal insulation, serves as an energy reservoir, and mechanically anchors the skin to underlying musculoskeletal structures while cushioning mechanical impacts (Fore, 2006).

Intrinsic skin aging is a series of chronologically physiological changes primarily driven by genetic and hormonal factors. This process involves a cascade of molecular dysregulations, including DNA damage, telomere shortening, excessive ROS production, and mitochondrial dysfunction, which collectively drive the accumulation of senescent cells in tissues and thereby contribute to progressive senescence (Salminen et al., 2022). Age-dependent functional deterioration occurs across all skin strata—epidermis, DEJ, and dermis. Epidermal aging is characterized by diminished keratinocyte proliferative capacity, resulting in progressive thinning of both the viable epidermis and stratum corneum (Low et al., 2021). Impaired keratinocyte differentiation characterized by the reduced synthesis of keratins and structural proteins compromises the epidermal barrier integrity and hydration capacity (Wang et al., 2020). Age-related declines in keratinocyte migratory potential further disrupt reepithelialization during wound healing, resulting in delayed tissue repair (Ross et al., 2011). In addition, cellular attrition exacerbates epidermal atrophy, with melanocyte populations reportedly decreasing by 8%–20% per decade (Gilchrest et al., 1979). Intrinsic skin aging also manifests through structural alterations in the dermal papillae and basal layer, characterized by progressive thinning. This anatomical remodeling induces DEJ flattening, thereby reducing the interfacial contact area between dermal and epidermal compartments. As a consequence, the diminished exchange surface impairs nutrient diffusion to the epidermis while suppressing basal keratinocyte proliferative capacity (Russell-Goldman and Murphy, 2020; Sauermann et al., 2002).

During intrinsic aging, the dermis exhibits a progressive decline in the number and functional capacity of fibroblasts. This cellular deterioration leads to the diminished synthesis of collagen and elastic fibers, thereby contributing to cutaneous laxity and wrinkle formation (Freitas-Rodríguez et al., 2017; Kohl et al., 2011). Fibroblast senescence also contributes to skin aging by secreting a senescence-associated secretory phenotype, which decreases proliferation by impeding the release of essential growth factors and enhances the degradation of the ECM by activating matrix metalloproteinases (MMPs) (Ghosh and Capell, 2016). The ROS produced during aging are the main stimuli increasing MMP levels in aging skin, leading to collagen degradation and fibroblast senescence. Aged fibroblasts also produce additional ROS, further promoting MMP expression and forming a vicious cycle that accelerates dermal aging. This process severely hinders mechanical interactions between fibroblasts and ECM, resulting in reduced fibroblast volume (Freitas-Rodríguez et al., 2017; Shin et al., 2019). The functional decline and volume reduction of dermal fibroblasts are important reasons for the slowed wound healing in aged skin (Boismal et al., 2020).

Skin aging is not solely driven by intrinsic factors; long-term exposure to solar UV radiation is the primary cause of extrinsic skin aging, also known as photoaging, which accounts for approximately 80% of total skin aging (Friedman, 2005). Photoaging and intrinsic aging overlap, causing areas frequently exposed to sunlight, such as the face, neck, forearms, and dorsal hands, to exhibit premature aging phenotypes compared with photoprotected skin (Rittié and Fisher, 2015). Photoaged skin is clinically characterized by distinct pathological features, including leathery texture, deep rhytides, telangiectasia (“broken” capillaries), mottled hyperpigmentation, and lentigines, and is in stark contrast to skin that predominantly undergoes intrinsic aging (Brooke et al., 2001). UV radiation is classified into the three subtypes based on wavelength, biological activity, and cutaneous penetration: long-wave UVA (320–400 nm), medium-wave UVB (280–320 nm), and short-wave UVC (200–280 nm) (Dorf and Maciejczyk, 2024). Despite being a weak mutagen, UVA penetrates deeply into the dermal and subcutaneous layers due to its long wavelength, acting as the principal driver of photoaging through sustained oxidative damage (Battie et al., 2014). By contrast, UVB radiation, though limited to epidermal absorption due to its short wavelengths, exhibits potent genotoxicity by directly inducing thymine dimer photoproducts that cause DNA damage, thereby initiating mutagenic processes and carcinogenesis (Guan et al., 2021). UVC demonstrates the strongest mutagenic potential but is effectively filtered by the stratospheric ozone under normal atmospheric conditions and thus fails to reach the Earth’s surface (Dorf and Maciejczyk, 2024).

UV radiation initiates a cascade of molecular and cellular events that drive accelerated skin aging. It induces ROS generation, resulting in oxidative stress and DNA damage. Concurrent inflammatory pathway activation, MMP upregulation, and disrupted collagen/elastin synthesis further exacerbate cutaneous degeneration and elasticity loss (Cai et al., 2023). A hallmark histological feature of photoaging is the accumulation of abnormally thickened and fragmented elastic fibers, termed “solar elastosis” (Tsuji, 1980). Extrinsic aging also induces a drastic reduction in type I collagen and an increase in type III collagen deposition. This imbalance in the I/III collagen ratio renders aged skin fragile and inelastic (Dorf and Maciejczyk, 2024). The epidermal rete of photoaged skin is thicker than that of chronologically aged skin, and epidermal atrophy is observed in severely photoaged skin (Bhawan et al., 1995). UV radiation-induced keratinocyte damage reduces cellular activity and decelerates epidermal turnover, leading to compromised barrier function. This effect manifests clinically as severe xerosis (dryness) and desquamation, with UV-driven effects often surpassing the severity of intrinsic aging phenotypes (Farage et al., 2013). As a photoprotective mechanism, melanogenesis is upregulated to counteract UV-generated ROS (Eller et al., 1994). However, chronic sun exposure promotes uneven pigmentation in aged skin that frequently progresses to solar lentigines, which are characteristic hyperpigmented lesions pathognomonic of photoaging (Black, 2016; Rittié and Fisher, 2015). Furthermore, excessive UV exposure increases melanoma risk through melanocytic malignant transformation, while age-related remodeling of the tumor microenvironment during physiological senescence further enhances susceptibility, establishing melanoma as a critical event in cutaneous aging (Tsai and Chien, 2022; Urban et al., 2021). Finally, photoaging accelerates the loss of subcutaneous fat, weakening the skin’s supportive structure and leading to increased sagging and hollowing of the skin (Scharffetter-Kochanek et al., 2000).

Autophagy is a highly conserved cellular degradation and recycling process present in all eukaryotic organisms. In mammalian cells, autophagy primarily includes three types: chaperone-mediated autophagy (CMA), microautophagy, and macroautophagy. These types all facilitate the proteolytic degradation of cytoplasmic components within lysosomes, but their transport mechanisms differ (Mizushima and Komatsu, 2011; Yang and Klionsky, 2010). In CMA, targeted proteins are translocated across the lysosomal membrane by complexing them with chaperone proteins (such as HSC-70), which are recognized by the lysosomal membrane receptor lysosomal-associated membrane protein 2A, resulting in their unfolding and degradation (Saftig et al., 2008). In microautophagy, invaginations or protrusions of the lysosomal membrane are used to capture cargo, and the uptake occurs directly at the limiting membrane of the lysosome (Parzych and Klionsky, 2014). Macroautophagy (hereafter referred to as autophagy) is the most extensively studied type to date. It is the engulfment of large structures through selective and nonselective mechanisms and is characterized by the formation of autophagosomes. This process involves three key steps: initiation, nucleation, and elongation, each of which is regulated by multiple critical genes and signaling pathways (Cao et al., 2021). Stress signals that trigger autophagy typically encompass starvation, hypoxia, oxidative stress, protein aggregation, and endoplasmic reticulum (ER) stress (Glick et al., 2010). A classic example is starvation-induced autophagy, where a reduction in nutrient supply leads to bioenergetic stress and elevated AMP levels. This phenomenon activates AMP-activated protein kinase (AMPK), which subsequently inhibits the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 inhibition promotes the assembly of the UNC-51 like kinase 1 (ULK1) complex, which comprises ULK1 (homologous to yeast autophagy-related gene 1 (ATG1)), ATG13, ATG101, and focal adhesion kinase family interacting protein of 200 kDa (FIP200). In response to stress signaling, the ULK1 complex is recruited to the phagophore assembly site on the ER, initiating autophagosome formation (Xue et al., 2024). Conversely, the presence of nutrients and growth factors activates mTORC1, leading to the phosphorylation of autophagy-related proteins and the suppression of autophagy (Kim and Guan, 2015; Wang and Zhang, 2019). In the second step, the activated ULK1 complex induces phagophore nucleation by promoting the production of phosphatidylinositol 3-phosphate (PI3P) through the formation of a supramolecular complex with class III phosphoinositide 3-kinase (PI3K) activity. This complex consists of VPS34, VPS15, ATG14, Beclin-1, autophagy and Beclin-1 regulator 1 (AMBRA1), and/or UV radiation resistance-associated gene (UVRAG). It accompanies the recruitment of ATG9-containing vesicles, and its activity is subjected to tonic inhibition by B-cell lymphoma-2 (Bcl-2). Finally, in the phagophore elongation step, ATG7 and ATG10 catalyze the formation of the ATG12–ATG5–ATG16L1 complex. At the same time, ATG4, ATG7, and ATG3 cooperate to cleave the precursor of microtubule-associated protein light chain 3 (LC3)-like proteins into their mature forms, which are then conjugated with phosphatidylethanolamine (PE) and recruited to the autophagosome with the support of WD-repeat protein interacting with phosphoinositide (WIPI) proteins. LC3 and LC3 homologs enable the autophagosome to bind to autophagy substrates and/or mediate cargo-selective proteins, including p62 (Galluzzi and Green, 2019; Xue et al., 2024). Upon completion, the phagophore is sealed to form the characteristic double-membrane autophagosome. As autophagy progresses, autophagosomes fuse with lysosomes to form autolysosomes. This fusion enables progressive acidification, consequently activating lysosomal hydrolases that mediate substrate degradation. The resulting breakdown products are released back into the cytoplasm for reuse or to provide energy (Choi et al., 2013).

Autophagy serves as a pivotal regulator of cutaneous homeostasis, functioning as a critical mechanism of intracellular quality control for keratinocytes, fibroblasts, and melanocytes (Sukseree et al., 2013). Under physiological and stress conditions, autophagy facilitates the clearance of senescent organelles and misfolded proteins, thereby modulating skin cell functionality and delaying aging progression (Vikram et al., 2024; Wang et al., 2019b; Zhong et al., 2024). For instance, the autophagy inducer heptasodium hexacarboxymethyl dipeptide-12 (Aquatide™) enhances oxidative stress resistance in normal human epidermal keratinocytes in vitro while clinically improving skin elasticity and texture (Lim et al., 2019). Similarly, rapamycin (mTOR inhibitor) attenuates UVB-induced fibroblast photoaging by activating autophagy to suppress ROS accumulation (Qin et al., 2018). Preclinical studies revealed that a variety of naturally derived bioactive compounds exert significant anti-aging effects on the skin through a multitarget regulation of the autophagy pathway (Li et al., 2018; Lin et al., 2024; Yang et al., 2023). Moreover, skin aging is closely linked to and partially driven by autophagy defects (Eckhart et al., 2019). ATG7-deficient keratinocytes have exhibited increased DNA damage and senescence markers following oxidative stress induced by paraquat, a cellular senescence-inducing oxidant (Song et al., 2017). Autophagy deficiency is strongly associated with premature senescence and oxidative damage accumulation in melanocytes (Ni et al., 2016; Setaluri, 2015; Zhang et al., 2015). Furthermore, chronic and repeated UVA exposure disrupts lysosomal function in skin fibroblasts, impairing intracellular degradation mechanisms and contributing significantly to photoaging (Huang et al., 2019).

Despite these compelling data, some studies took the opposite view and suggested that autophagy activation may promote skin aging. A significant increase in autophagy vesicles was observed in senescent fibroblasts (Gerland et al., 2003), and an increase in autophagic activity was reported in senescent human keratinocytes induced by ROS (Gosselin et al., 2009). These findings suggest that cells may enhance autophagic activity in response to stress to cope with damage and restore survival (protective autophagy). However, this activity may lead to the accumulation of damaged cells, thereby promoting aging. Several studies supported this view. Young et al. (2009) demonstrated that oncogene-induced fibroblast senescence depends on prior autophagic activity, and reducing autophagic expression levels through pharmacological or genetic approaches can inhibit the onset of senescence. Similarly, ATG5 overexpression has been shown to reduce the proliferation of melanoma cells and induce senescence, while autophagy inhibition delays oncogene-induced senescence (Liu et al., 2013). These results indicate that the role of autophagy in skin aging may exhibit a context-dependent duality. If autophagy is excessively activated or prolonged, it may lead to cell death due to the excessive elimination of essential cellular proteins or organelles. This phenomenon explains why autophagy is also referred to as type II programmed cell death (type I being apoptosis) (Lin et al., 2024; Tsujimoto and Shimizu, 2005). Autophagic flux-dependent outcomes have been observed in cutaneous oncology. Studies found that in senescent human keratinocytes, excessive autophagy activation can induce senescent cell death, thereby inhibiting tumors; whereas moderate autophagy activation facilitates the escape of senescent cells from death and promotes the growth of tumor cells (Deruy et al., 2014). This phenomenon has also been widely observed in melanoma (Pangilinan et al., 2024) (Figure 3). In summary, these findings position autophagy regulation as an essential therapeutic target for skin anti-aging interventions.

The signaling proteins of the MAPK pathway mainly belong to the family of serine/threonine protein kinases; this pathway is a key cellular signal transduction mechanism widely involved in the regulation of cell proliferation, differentiation, stress response, and apoptosis and other biological processes (Pearson et al., 2001). It comprises three main classes of kinases: mitogen-activated protein 3 kinase (e.g., Raf), mitogen-activated protein 2 kinase (e.g., MEK) and MAPK. Among the pathways of MAPK family, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to 3), and p38 MAPK (α, β, γ, and δ) are the most widely studied. By activating upstream signals through external stimuli (such as growth factors, cytokines, neurotransmitters, hormones, and cellular stress), the MAPK signaling pathway can regulate the expression of downstream target genes and thereby influence cellular physiological states (Cargnello and Roux, 2011; Gaestel, 2015).

MAPK is important in skin aging and is primarily activated by the ROS generated in response to age-related mitochondrial dysfunction and external factors, such as UV radiation (Chaiprasongsuk and Panich, 2022; Shin et al., 2019) (Figure 4). The heterodimer activator protein 1 (AP-1) composed of c-Fos and c-Jun is a key transcription factor that regulates the expression of MMP-1, MMP-3, and MMP-9, resulting in collagen degradation. The expression of c-Jun and c-Fos is regulated by the MAPK signaling pathways, with ERK stimulating c-Fos expression; meanwhile, the activation of p38 and JNK is essential for c-Jun expression (Chiang et al., 2013; McBride and Nemer, 1998; Pramanik et al., 2003). The MAPK-induced activation of AP-1 suppresses TGF-β signaling, a key regulator of ECM biosynthesis (Gao et al., 2018; Pittayapruek et al., 2016). TGF-β enhances collagen synthesis and inhibits its degradation by downregulating MMPs through the Smad pathway and upregulating the tissue inhibitors of metalloproteinases (TIMPs) (Shin et al., 2019; Verrecchia and Mauviel, 2002). NF-κB is another important MMP transcription factor activated by the MAPK signaling (Baek et al., 2024). NF-κB activity upregulates MMPs such as MMP-1 and MMP-3 in dermal fibroblasts (Lee et al., 2012; Park et al., 2014). In addition, ROS and activated MAPK signaling pathways facilitate the dissociation of the NF-κB inhibitor protein IκB in the cytoplasm, leading to the translocation of NF-κB into the nucleus where it induces the expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and cyclooxygenase-2 (COX-2), contributing to skin damage and inflammatory responses (Bell et al., 2003; Han et al., 2022; Wang et al., 2019a). These pro-inflammatory cytokines could further induce the expression of MMPs (Nisar et al., 2022). Activated NF-κB upregulates the expression of heme oxygenase-1 (HO-1), indirectly increasing the levels of free iron in the cells and thereby promoting ROS production through the Fenton reaction (Kammeyer and Luiten, 2015; Li et al., 2019). The MAPK signaling can also mediate UVB-induced melanogenesis (Hu et al., 2019; Zhou et al., 2022). Its abnormal activation is a major cause of melanoma progression. For instance, UV radiation triggers the sequential activation of Ras, Raf, MEK, and ERK in cells, thereby regulating various carcinogenic biological activities (Guo et al., 2021).

Increasing evidence highlights a mechanistic interplay between the MAPK signaling pathway and autophagy that modulates the aging of key skin cell populations, such as keratinocytes, fibroblasts, and melanocytes (including melanoma) (Figure 5; Table 1). The specific mechanisms involved are detailed in the following subsections.