Researchers at Memorial Sloan Kettering Cancer Center have uncovered how the immune system can attack pathogens while protecting healthy tissue from collateral damage. In a study published in Nature, the team identified the enzyme DHRS7 as a regulator of the lipid signal 5-oxoETE. The signal helps recruit immune cells to sites of infection or injury, but it also activates a protective mechanism that limits unnecessary inflammation in healthy tissue. The discovery resolves a question that has remained open since 1992 and may inform future research into cancer, inflammatory bowel disease and asthma.
A missing enzyme gene puzzled scientists for decades
The story began in 1992, when researchers identified the lipid molecule 5-oxoETE as a signal that directs immune cells toward sites of infection or injury. They also observed an enzyme capable of producing and breaking down the molecule, but the human gene responsible for that enzyme remained unknown. MSK researcher Yanan Ma and colleagues tested candidate genes in human cells. When they disabled DHRS7, the enzyme’s activity disappeared, identifying the gene involved in the pathway.
Zebrafish revealed an unexpected protective role
Rather than relying only on mice, the researchers used zebrafish to study the full immune response. Mice lack a known immune-cell receptor for 5-oxoETE, making them unsuitable for investigating the complete pathway. Zebrafish retain the relevant receptor and biological machinery. When researchers disabled the receptor or DHRS7, the fish developed intestinal inflammation and cell death. The result showed that the pathway does more than recruit immune cells: it also protects healthy tissue from damage caused by the immune response itself.
How 5-oxoETE protects cells
The team found that 5-oxoETE promotes the expression of NUDIX hydrolases, enzymes that help remove oxidatively damaged nucleotide building blocks and protect cells from injury. The researchers propose that the DHRS7–5-oxoETE–OXER1 pathway adjusts its activity according to the cell’s NADP+/NADPH balance. At a wound, it helps activate an immune alert; in undamaged tissue, it can suppress unnecessary inflammation. This helps explain why disabling a signal associated with inflammation can paradoxically make tissue inflammation worse.
Medical applications remain a research question
The findings could provide new directions for research into cancer, inflammatory bowel disease and asthma. The researchers said that strengthening tissue resilience to oxidative stress might eventually help reduce intestinal damage associated with radiation or chemotherapy. But the work was based mainly on zebrafish and human-cell experiments. It has not shown that manipulating the pathway is a safe or effective treatment for patients. Further studies will be needed to establish how the mechanism works in human disease and whether it can be translated into therapies.