Keratin is the fibrous, waterproof protein that builds everything from our hair and nails to a rhino’s horn. However, a tiny glitch in it can have problematic outcomes. A new study has found that changes in a keratin gene called KRT16 can lead to a rare condition known as pachyonychia congenita (PC). This disorder affects the skin, nails, and the lining of the mouth, and often causes painful, thick patches of skin—especially on the hands and feet.
PC is an outcome of an overactive immune response, so the researchers tested a medicated cream called ruxolitinib in mice with PC-like skin lesions. They discovered that the cream could successfully soothe the overactive immune signals and reduce the thickness of the skin lesions by about 25% in just one week. The findings are published in Science Translational Medicine.
Investigating K16’s role in skin health
The outer layer of our skin is built from keratinocytes—epidermal cells that produce keratin—and they are constantly coping with environmental stress and injury.
For years, keratin was thought to simply provide cells with structural strength, like a biological scaffold. Several new studies now reveal a more dynamic role: these proteins also act as internal managers, helping control how cells grow and how the immune system responds under pressure.
Healthy skin depends on a balanced exchange between skin cells and the immune system. In this study, researchers aimed to understand how skin cells control this interaction and recruit immune cells to keep responses in check and prevent disease.
To do so, they focused on Keratin 16 (K16), which is often used as a telltale sign of several inflammatory skin conditions, including psoriasis, atopic dermatitis, and rare genetic disorders such as PC.
To understand how K16 controls the skin’s immune system, the researchers took a three-pronged approach—combining human data, animal experiments, and cell studies. The team started by examining skin biopsies and genetic data from PC and psoriasis patients, comparing diseased to healthy skin to map how K16 levels correlated with immune activity.
They then bred mice lacking the K16 protein and used CRISPR to knock out K16 in human cells, creating new cell lines in the lab. Finally, they exposed these cells to a virus-like trigger to test whether the absence of K16 would cause an exaggerated immune response.
Skin lesions showed a hyperactive interferon response—an immune alarm stuck on high—revealing that the disease involves more than just structural damage.
K16 normally acts as a brake on this system by directly binding to proteins that regulate the interferon pathway, helping keep immune signaling from going into overdrive. In these diseased areas, however, K16 was found clumped rather than functioning properly, suggesting mutations in it can prevent it from performing this regulatory role.
Both mouse models and human cells reinforced K16’s key role: when it is absent or altered, interferon signals surge and inflammation ramps up.
This discovery showed that PC is driven by an overactive immune system, pointing to new ways to switch that alarm off. Building on this, researchers proposed using ruxolitinib (Opzelura), a medicated cream already designed to calm immune signals. As a Janus kinase (JAK) inhibitor, the cream blocks the signals that trigger immune-driven inflammation, reducing PC symptoms by about a quarter within just a few days.