Photophagy: Unveiling a Novel Cellular Mechanism in UVB‐Induced Skin Aging and Resilience

1. Introduction

The skin is consistently exposed to solar ultraviolet (UV) radiation, serving as the primary barrier against environmental insults. While the harmful effects of UVB exposure, such as DNA damage, oxidative stress, and inflammation compromising skin integrity, are well documented, emerging research has revealed novel cellular responses that modulate these processes. One such pathway, which remains underexplored, is light‐induced autophagy, referred to here as photophagy. This term describes autophagic responses triggered explicitly by light, in this case, UV radiation affecting the skin. Light‐induced autophagy represents an adaptive cellular mechanism that maintains homeostasis under photostress. However, its precise role in skin photodamage remains largely uncharted. Although few studies have examined the light‐driven autophagy response in the skin, limited research has been reported regarding the role of this cellular signaling response in relation to cell death and repair in UVB‐exposed skin. This brief viewpoint explores the role of light‐induced autophagy in regulating the response of skin to UVB‐induced photodamage and highlights its potential as a therapeutic target for developing novel anti‐photodamage strategies.

2. Light‐Induced Autophagy and UV‐Induced Damage: A Molecular Perspective

Skin, the body's largest organ, serves as the first line of defense against various environmental aggressors, including solar radiation, pollutants, and pathogens. Among these, UV radiation, particularly UVB (290–315 nm), poses a significant threat by inducing photodamage that manifests as inflammation, hyperpigmentation, premature aging, and carcinogenesis. Chronic UVB exposure leads to cumulative DNA damage, mitochondrial dysfunction, and oxidative stress, all compromising skin structure and function. Autophagy is a well‐conserved signaling process that facilitates the removal of damaged organelles and proteins, thereby preserving cellular function. Under UVB exposure, autophagic flux is rapidly activated in keratinocytes and dermal fibroblasts at low UVB doses, leading to the clearance of photodamaged macromolecules [1]. Previously studied in the context of starvation or infection, autophagy is now increasingly recognized for its role in photoprotection. Intriguingly, UV radiation induces a specialized form of autophagy, called photophagy or light‐induced autophagy. Light‐induced autophagy is uniquely sensitive to light cues and engages specific molecular mediators to restore cellular homeostasis under phototoxic stress. It plays a dual role in protecting against acute phototoxicity by degrading oxidized proteins and repairing damage, while potentially contributing to chronic skin aging, if dysregulated [2]. Recent studies have linked defective autophagic responses to enhanced UVB‐induced apoptosis, suggesting that light‐induced autophagy might act as a cytoprotective mechanism to clear damage from cells. For example, the knockdown of key autophagy regulators exacerbates UVB‐induced cell death, reinforcing the idea that light‐induced autophagy is essential for cellular survival under photostress. However, excessive or impaired autophagy has also been implicated in photoaging and photocarcinogenesis, raising concerns about its long‐term impact on skin health.

Autophagy is a tightly regulated multistep process involving initiation, nucleation, elongation, and degradation phases. Key proteins such as ULK1, Beclin‐1, LC3, and p62 coordinate the formation of autophagosomes, which engulf damaged organelles and proteins. Upon fusion with lysosomes, the contents are degraded and recycled. In keratinocytes and dermal fibroblasts, low‐dose UVB exposure rapidly enhances autophagic flux, facilitating the removal of photodamaged macromolecules. Light‐induced autophagy can therefore be viewed as an adaptive mechanism activated by UVB‐induced reactive oxygen species (ROS). It serves dual roles: as a cytoprotective process that preserves mitochondrial function, protein quality, and DNA integrity; and potentially as a contributor to chronic degeneration when dysregulated. Knockdown studies targeting autophagy‐related genes (e.g., ATG5 and ATG7) demonstrate increased susceptibility to UVB‐induced apoptosis, underscoring the protective role of light‐induced autophagy. However, persistent or excessive autophagy may lead to the degradation of essential cellular components, contributing to photoaging and tissue atrophy.

3. Light‐Induced Autophagy and Planar Cell Polarity Disruption in Skin

An intriguing and previously unexplored dimension of UV‐induced cellular response is the potential interplay between light‐induced autophagy and planar cell polarity (PCP) pathways. PCP regulates the coordinated spatial orientation of cells within the epidermis, playing a critical role in maintaining tissue architecture, directional cell migration, and wound healing. While numerous molecular components of autophagy have been implicated in skin barrier integrity, UV response, and tumor suppression, their intersection with PCP signaling under photostress has not yet been systematically investigated. Core PCP regulators such as Frizzled (FZD), Van Gogh‐like (VANGL), and CELSR1 are sensitive to UVB‐induced disruption, which affects cytoskeletal organization, cell cohesion, and intercellular lipid structures, thereby compromising the biomechanical resilience of the skin [3]. Notably, autophagy has been shown to target protein complexes under oxidative stress, raising the possibility that light‐induced autophagy may contribute to the degradation of PCP components and exacerbate structural disorganization. Conversely, it may also act as a repair mechanism to remove damaged elements and restore polarity. UVB‐induced inhibition of keratinocyte motility and altered focal adhesion dynamics suggest that cytoskeletal remodeling is a key target of this response [4]. The intersection of light‐induced autophagy and PCP signaling presents a promising yet underexplored avenue for understanding how UVB‐induced autophagic activity influences skin homeostasis. A critical question is whether light‐induced autophagy functions as a reparative process, selectively clearing damaged PCP components to restore epidermal structure, or if it inadvertently contributes to further disruption of PCP signaling, thereby intensifying photodamage. Clarifying this relationship could uncover novel mechanisms by which the skin responds to UV stress and reveal new therapeutic targets for preserving epidermal integrity. Further research is needed to determine whether modulating autophagy can help maintain PCP architecture and improve regenerative outcomes following photodamage.

Given the speculative link between autophagy and PCP, several targeted experimental strategies could help elucidate this interaction. Gene knockdown approaches or autophagy flux assays in PCP‐deficient models may provide insights into the mechanistic relationship between these pathways. Co‐localization studies using immunofluorescence to visualize PCP proteins (e.g., VANGL, CELSR1, and FZD) alongside autophagy markers (e.g., LC3 and p62) in keratinocytes or 3D skin models post‐UVB exposure could determine whether PCP components are sequestered into autophagosomes. Pharmacological modulation of autophagy using agents such as chloroquine or rapamycin, as well as genetic suppression via ATG5 or ATG7 knockdown, could further clarify how autophagy influences PCP protein dynamics. Generating PCP‐deficient keratinocyte lines (e.g., CELSR1‐KO and VANGL2‐KO) would allow for a comparative assessment of autophagic flux following UVB exposure. In vivo, mouse models with epidermis‐specific deletions in autophagy genes could be used to evaluate PCP organization in skin tissues through histological and confocal imaging techniques. Additionally, transcriptomic or proteomic profiling of UVB‐exposed skin or cells with altered autophagic activity may uncover differential regulation of PCP‐associated genes or pathways. Finally, time‐lapse microscopy offers a dynamic platform to monitor the real‐time effects of autophagy modulation on cell polarity, migration, and cytoskeletal remodeling in keratinocytes.

4. Light‐Induced Autophagy in Photocarcinogenesis: Friend or Foe?

While light‐induced autophagy is widely recognized for its cytoprotective role, particularly in clearing oxidized DNA, reducing inflammation, and maintaining skin homeostasis during early photodamage, its function in photocarcinogenesis is complex and context‐dependent. Many core autophagy components are already implicated in skin barrier maintenance and UV‐response pathways; however, their role in tumor development under chronic UVB exposure remains an area of active investigation. Persistent or dysregulated light‐induced autophagy may inadvertently support the survival of mutated or pre‐malignant cells, promoting genomic instability and tumor progression (Figure 1). Melanoma studies, for instance, show that tumor cells leverage autophagy for survival under metabolic stress. Similar mechanisms may apply to light‐induced autophagy, which can sustain energy production by degrading oxidized organelles. Inhibiting autophagy in these contexts sensitizes tumors to chemotherapy and immune responses [5]. As such, therapeutic modulation of light‐induced autophagy must be approached with caution. Pharmacologic agents such as chloroquine and rapamycin have shown potential in modulating autophagy pathways, making them attractive candidates for influencing skin responses to stress. However, their efficacy and safety profiles have not been thoroughly evaluated in the specific context of chronic UVB exposure. Long‐term exposure to UVB presents a unique oxidative and inflammatory challenge that may alter drug responses. Thus, further in vivo studies are needed to understand their role in mitigating photoaging or enhancing cutaneous resilience. A deeper understanding could open avenues for targeted photoprotective therapies. Future research should also clarify how light‐induced autophagy modulates carcinogenic risk in UV‐exposed skin and whether its modulation can be harnessed without compromising protective functions. Balancing the protective and oncogenic roles of light‐induced autophagy is critical for developing effective interventions. Moreover, combining light‐induced autophagy modulation with antioxidants, anti‐inflammatories, and barrier‐repair agents may offer synergistic benefits. Future research should prioritize mechanistic studies that dissect the specific pathways through which light‐induced autophagy influences skin physiology and pathology.

FIGURE 1.

UVB‐induced autophagy and cellular responses intricately regulate skin homeostasis. This schematic represents the effects of UVB exposure on skin cells. Acute or chronic UVB exposure induces ROS‐mediated ER stress, activating the unfolded protein response (UPR) in a context‐dependent manner. This results in disruptions in planar cell polarity, stem cell function, and autophagy regulation, influencing DNA repair, apoptosis, and skin aging. While autophagy can facilitate DNA repair and restore homeostasis, its impairment contributes to inflammaging and tissue disorganization.

5. Conclusion and Future Directions

Light‐induced autophagy represents a critical cellular response to UVB‐induced skin damage, embodying protective and potentially harmful roles. Autophagic regulation of DNA repair, inflammation, PCP, and carcinogenesis underscores its importance in skin biology. Understanding the molecular mechanisms of light‐induced autophagy and its context‐specific outcomes is essential for developing precision interventions. As our knowledge deepens, harnessing light‐induced autophagy may become a cornerstone of innovative strategies to enhance skin health and combat UV‐related disorders. Future studies should focus on defining the molecular regulators of light‐induced autophagy under UV exposure and identifying potential therapeutic targets. Given its dualistic nature, fine‐tuning light‐induced autophagy in the skin could provide new strategies for preventing photoaging and photocarcinogenesis while preserving epidermal homeostasis. While light‐induced autophagy more accurately reflects current understanding, we propose photophagy as a potential conceptual term to describe UV‐induced autophagic responses, warranting further discussion and validation in future studies.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.