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Review
. 2025 Jun 27:13:1625357.
doi: 10.3389/fcell.2025.1625357. eCollection 2025.

Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications

Xu Liu  1 , Bo Chen  2 , Xuefeng Liu  3 , Xiaoqing Zhang  4 , Jingdong Wu  1   5
Affiliations
Review

Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications

Xu Liu et al. Front Cell Dev Biol. .

Abstract

Skin aging manifests as structural degradation, functional decline, and heightened disease susceptibility. Central to this process is the overactivation of the mitogen-activated protein kinase (MAPK) signaling pathway triggered by reactive oxygen species (ROS). Autophagy, a lysosomal degradation mechanism essential for maintaining cellular homeostasis, demonstrates context-dependent duality in skin aging by mediating cytoprotective effects and stress-induced dysfunction. Emerging evidence highlights that the interplay between MAPK signaling and autophagy critically modulates skin aging progression. Despite its therapeutic potential, the lack of effective targeting strategies severely hinders clinical translation. Therefore, this review synthesizes current evidence on MAPK-autophagy interplay across key cutaneous cell populations, namely, keratinocytes, fibroblasts, and melanocytes (including melanoma), revealing cell-type-specific regulatory networks that influence skin aging. Subsequently, we explore the therapeutic potential of natural bioactive compounds targeting this interplay to accelerate the translation of evidence into the progression of strategies for combating skin aging.

Keywords: MAPK; autophagy; interplay; natural bioactive compounds; skin aging.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Literature search flowchart (using PubMed as an example).
FIGURE 2
FIGURE 2
Schematic of the characteristics of young and aged skin. Under the combined influence of intrinsic and extrinsic factors, aging skin undergoes a series of complex structural and functional changes: (a) Epidermal dehydration and impaired barrier function; (b) Proliferation, differentiation, and migration abilities of keratinocytes weaken; (c) Decreased number and declined function of melanocytes, leading to abnormal melanin production and increased risk of melanoma; (d) Flattened DEJ with weakened structural integrity; (e) Senescent changes in the fibroblasts in the dermis, characterized by a reduction in number and functional decline, leading to the decreased synthesis and increased degradation of ECM components such as collagen and elastic fibers and thereby disrupting the dermal reticular structure; (f) Induced inflammation; (g) Compromised integrity of the microvascular network, resulting in vascular fragmentation; (h) Atrophied subcutaneous adipose tissue, accompanied by a reduction in adipocyte numbers. These changes collectively contribute to the characteristic manifestations of skin aging. (Created with BioRender.com).
FIGURE 3
FIGURE 3
Molecular mechanisms of autophagy and its dual role in skin aging. Autophagy mediates cytosolic cargo clearance through double-membrane autophagosome formation, lysosomal degradation, and metabolite recycling, exhibiting dual regulatory roles in skin aging and associated tumor progression. (Created with BioRender.com).
FIGURE 4
FIGURE 4
Diagram of MAPK-mediated skin aging. Phosphorylated MAPK, activated by ROS, inhibits collagen production; promotes inflammatory responses, melanogenesis, and melanoma progression; and ultimately accelerates skin aging.↑, upregulation; ↓, downregulation (Created with BioRender.com).
FIGURE 5
FIGURE 5
Summary of the role of the MAPK–autophagy interplay in skin aging. Under stress conditions, the interplay between the MAPK signaling and autophagy plays a crucial regulatory role in key skin cell populations: in keratinocytes, it regulates cell proliferation, differentiation, and migration, influencing epidermal barrier function and the expression of aging-related biomarkers; in skin fibroblasts, it primarily modulates the crosstalk between autophagy and apoptosis and collagen synthesis and degradation, participating in skin aging; in melanocytes (a) it regulates melanogenesis (black pathway) and degradation (red pathway); and in melanoma (b) it exhibits pro-tumor (green pathway) and anti-tumor (black pathway) effects by modulating the balance between cell death and survival. In the diagram, the differently colored lines illustrate the regulatory mechanisms mediated by the interplay of specific MAPK subtypes and autophagy, and the dotted lines represent the overall activation/inhibition of the MAPK pathway.↑, upregulation; ↓, downregulation (Created with BioRender.com).
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