Researchers found that sunburn disables a natural skin defense, allowing inflammation to trigger dangerous changes in cells. Understanding this process could help stop skin cancer before it starts.
Sunlight plays an essential role in human health by helping the body produce key nutrients such as vitamin D. At the same time, excessive time in the sun can sharply raise the risk of developing skin cancer.
A new study published in Nature Communications describes how long-term exposure to ultraviolet (UV) radiation can set off inflammation inside skin cells by breaking down an important protective protein called YTHDF2. This protein helps keep healthy skin cells from becoming cancerous. The research shows that YTHDF2 is critical for managing RNA activity inside cells, which helps maintain normal cellular function. These insights point toward possible new ways to prevent or treat skin cancer.
How Unchecked Inflammation Fuels Skin Cancer
Nearly 5.4 million people in the United States are diagnosed with skin cancer each year, and more than 90% of cases are linked to too much UV exposure. UV radiation can harm DNA and create oxidative stress in skin cells, which sparks inflammation – causing redness, pain, and blistering that most people recognize as sunburn.
“We’re interested in understanding how inflammation caused by UV exposure contributes to the development of skin cancer,” said Yu-Ying He, PhD, Professor of Medicine in the Section of Dermatology at the University of Chicago.
RNA, short for ribonucleic acid, is a vital molecule that helps cells use genetic instructions to make proteins. Some RNAs, called non-coding RNAs, do not produce proteins but instead control how genes are turned on or off. These molecules usually work in the nucleus, where DNA is stored, or in the cytoplasm, where much of the cell’s activity takes place.
Loss of a Key Protein Pushes Cells Toward Cancer
He’s laboratory examines how environmental factors such as UV radiation and arsenic in drinking water disrupt cellular systems and lead to cancer. By analyzing multiple enzymes, the researchers discovered that UV exposure sharply reduces levels of YTHDF2. This protein is known as a “reader” because it recognizes RNA molecules marked with a chemical modification called N6-methyladenosine (m6A).
“When we removed YTHDF2 from skin cells, we saw that UV-triggered inflammation was much worse,” He said. “This suggests that the YTHDF2 protein plays a key role in suppressing inflammatory responses.”
While inflammation is necessary to fight infections, it can also contribute to serious diseases, including cancer, when it is not properly controlled. Scientists still have much to learn about how inflammation is regulated, especially after damage caused by UV radiation.
Non-Coding RNA and an Unexpected Immune Trigger
Using multi-omics approaches and additional cell experiments, the team found that YTHDF2 binds to a specific non-coding RNA called U6. This RNA carries an m6A modification and belongs to a group known as small nuclear RNA (snRNA). Under UV stress, cancer cells contained higher levels of U6 snRNA, and these modified RNAs were shown to interact with toll-like receptor 3 (TLR3), an immune sensor that can activate inflammatory pathways linked to cancer.
Unexpectedly, these interactions took place inside endosomes. These compartments usually help recycle cellular material and are not where U6 snRNA is normally found.
“We spent a lot of time figuring out how these non-coding RNAs get to the endosome, since that’s not where they usually reside,” He explained. “For the first time, we showed that a protein called SDT2 transports U6 into the endosome, and YTHDF2 travels with it.”
A Cellular Surveillance System That Limits Damage
When YTHDF2 and m6A-modified U6 RNA reach the endosome together, YTHDF2 prevents the RNA from activating TLR3. If YTHDF2 is missing – such as after UV damage – the RNA can bind to TLR3 and trigger excessive inflammation.
“Our study uncovers a new layer of biological regulation, a surveillance system through YTHDF2 that helps protect the body from excessive inflammation and inflammatory damage,” He said.
The researchers say this discovery could lead to new approaches for preventing or treating UV-induced skin cancer by targeting the interactions between RNA and proteins that control inflammation.
Reference: “YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis” by Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, Chuan He and Yu-Ying He, 12 November 2025, Nature Communications.
DOI: 10.1038/s41467-025-64898-7
Additional authors include Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, and Chuan He from the University of Chicago.
The study was supported by grants from the National Institutes of Health, the University of Chicago Medicine Comprehensive Cancer Center, the ChicAgo Center for Health and EnvironmenT (CACHET), and the University of Chicago Friends of Dermatology Endowment Fund.
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2 Comments
If they figure out how to suppress that inflammatory response, what are the odds that more people will use the treatment to get the response under control so they can tolerate more sun, instead of using it to reduce their risk of getting melanoma?
BS