A new study in Nature Communications shows that sunburn-driven UV exposure degrades the protective protein YTHDF2 in skin cells, lifting suppression on inflammatory responses and contributing to cancer risk.

Researchers identify a non-coding RNA, U6 snRNA, carrying an m6A modification that binds to TLR3 inside endosomes when dysregulated, triggering inflammatory pathways linked to cancer.

YTHDF2 normally binds m6A-modified U6 RNA and, with SDT2, ferries it to endosomes to prevent TLR3 activation; loss of YTHDF2 lets U6 RNA spur excessive inflammation.

In normal skin, YTHDF2 regulates RNA metabolism by keeping U6 snRNA from activating the immune sensor TLR3, thereby reducing inflammation that can drive cancer.

UV exposure causes a two-step degradation of YTHDF2 via dephosphorylation and autophagic degradation, leading to U6 snRNA buildup and TLR3-driven inflammation that promotes tumor formation.

The study proposes targeting RNA–protein interactions that govern inflammation as a strategy to prevent or treat UV-induced skin cancer, framing a cellular surveillance system that limits damage.

Future work will expand on RNA–protein dynamics in inflammation and cancer and explore approaches to strengthen the skin’s natural defenses against UV exposure.

The findings highlight YTHDF2’s protective role in skin health and suggest that stabilizing YTHDF2 or blocking U6–TLR3 interactions could help prevent UV-related skin damage and carcinogenesis.

Given the global link between UV exposure and skin cancer, these insights point to new preventive and therapeutic directions centered on skin defense mechanisms.