30-year-old inflammation mystery solved as hidden cellular shield discovered

The mystery began in 1992, when researchers at McGill University observed an enzyme that could both produce and break down 5-oxoETE, a fatty signaling molecule that helps direct immune cells toward sites of infection. But the human gene responsible for making the enzyme could not be identified, making it difficult to study how problems with its activity might contribute to disease.

The breakthrough came when Yanan Ma, a postdoctoral researcher at MSK’s Sloan Kettering Institute, identified the gene DHRS7 as the source of the enzyme. Building on earlier work by former lab colleague King Lam Hui, Ma and Hui systematically switched off candidate genes in cultured human cells; disabling DHRS7 stopped the enzyme’s activity.

Ma then worked with zebrafish, which retain the 5-oxoETE receptor that mice lack. “This means that you can’t study the pathway in mice,” she said. “But the pathway is intact in fish. So picking the right alternative model was critical to advancing our understanding of how the human body responds.”

When Lengyel removed the receptor for 5-oxoETE, the zebrafish developed intestinal inflammation without infection. “So if you remove the receptor that detects the signal, you’d expect less inflammation, not more,” said Miklos Lengyel, a postdoctoral researcher who was studying colitis in zebrafish. The team later disabled DHRS7 in zebrafish, expecting inflammation to decrease, but instead observed an increase.

The paradoxical result pointed to a previously unrecognized function: the pathway also protects healthy cells from the toxic substances immune cells release to kill pathogens. “They flood the site with toxic substances to kill the bacteria,” said Philipp Niethammer. “But this can cause damage to healthy cells if it gets out of control.” The team traced the protection to enzymes called NUDIX hydrolases, which remove damaged DNA building blocks.

The findings could advance research into cancer, inflammatory bowel disease, and asthma. Mutations affecting DHRS7 and OXER1 have been identified in tumors of the gastrointestinal tract and uterus; mutations that prevent OXER1 from functioning properly have been linked to poorer outcomes in colorectal, pancreatic, and kidney cancers. “More research is needed, but there’s a possibility that activating the pathway could increase the resilience of the gut to oxidative stress—which might help counteract damage caused by radiation therapy or chemotherapy,” Lengyel said.

The research also connects to how physical injury triggers the same defensive chain. “What we are really studying is a pathway that integrates two completely different kinds of stress—mechanical and metabolic—and converts them into a single, coordinated, protective response,” Niethammer said.