Ceramides were identified as the molecular culprits behind acute kidney injury, damaging mitochondria and leading to organ failure.
Blocking ceramide metabolism completely protected kidneys in mice, offering hope for treating AKI and related diseases.
Ceramides a Key Trigger for Acute Kidney Injury
Acute kidney injury (AKI) is a sudden loss of short-term kidney function that can be fatal and can raise the likelihood of permanent chronic kidney disease. Triggers include severe infections such as sepsis and major procedures like heart surgery, and the condition strikes more than half of patients in intensive care units. No approved medications currently treat AKI.
Researchers at University of Utah Health (U of U Health) report that fatty molecules called ceramides set off AKI by harming mitochondria inside kidney cells. In mouse experiments, a backup drug candidate that alters how ceramides are processed protected mitochondrial structure and prevented kidney injury.
Reversing Kidney Damage:
“We completely reversed the pathology of acute kidney injury by inactivating ceramides,” says Scott Summers, PhD, distinguished professor and Chair of the Department of Nutrition and Integrative Physiology in the University of Utah College of Health and senior author on a paper describing the results. “We were stunned—not only did kidney function stay normal, but the mitochondria were unscathed,” Summers says. “It was truly remarkable.”
The results were published today (November 12) in Cell Metabolism.
An Early Warning Sign for Kidney Injury
The Summers lab had previously shown that ceramides can injure multiple organs, including the heart and liver. When the team measured ceramides in models of AKI, levels climbed steeply after kidney damage in both mice and human urine samples.
“Ceramide levels are very elevated in kidney injury,” says Rebekah Nicholson, PhD, first author on the study, who did the research as a graduate student in nutrition and integrative physiology at U of U Health and is now a postdoctoral fellow at the Arc Institute. “They go up quickly after damage to the kidneys, and they go up in relation to the severity of the injury. The worse the kidney injury is, the higher the ceramide levels will be.”
These results indicate that urinary ceramides could serve as an early biomarker for AKI, helping clinicians flag high-risk patients before symptoms emerge, including people undergoing heart surgery. “If patients are undergoing a procedure that we know puts them at high risk of AKI, then we can better predict whether or not they’re actually going to have one,” Nicholson says.
Modifying Ceramides Prevents Kidney Injury
By precisely altering the genetic program that produces ceramides, the team created mice that resisted AKI even under conditions that typically cause it. These “super mice” remained protected despite strong experimental stressors.
Preventive treatment with a new ceramide-lowering drug candidate from Centaurus Therapeutics, a company co-founded by Summers, also blocked kidney injury in mice. Kidney function improved, the animals stayed active, and kidney tissue appeared close to normal under a microscope. The research model puts significant strain on the kidneys, Nicholson notes, so “it’s really remarkable that mice were protected from the injury.”
“These mice looked incredible,” Summers adds.
The investigators determined that ceramides damage mitochondria, the cellular structures that generate energy. In injured kidney cells, mitochondria become misshapen and less efficient. Adjusting ceramide synthesis, either by genetics or with the drug, maintained healthy, working mitochondria even during stress.
Hope for Acute Kidney Injury and Beyond
Summers notes that the compound used in this study is closely related to, but distinct from, the ceramide-lowering drug already moving into human trials. He emphasizes that mouse data do not always predict outcomes in people and that safety must be established with further testing.
“We’re thrilled by how protective this backup compound was, but it’s still preclinical,” Summers says. “We need to be cautious and do our due diligence to make sure this approach is truly safe before moving it into patients.”
If the results translate to people, the team envisions giving the therapy ahead of time to individuals at high risk for AKI, such as those scheduled for heart surgery, a group in which about one quarter experience AKI.
Because the approach appears to work by preserving mitochondrial health, the researchers suspect it could have value for other conditions linked to impaired mitochondria.
“Mitochondrial problems show up in so many diseases—heart failure, diabetes, fatty liver disease,” Summers says. “So if we can truly restore mitochondrial health, the implications could be enormous.”
Reference: “Therapeutic remodeling of the ceramide backbone prevents kidney injury” by Rebekah J. Nicholson, Luis Cedeño-Rosario, J. Alan Maschek, Trevor Lonergan, Jonathan G. Van Vranken, Angela R.S. Kruse, Chris J. Stubben, Liping Wang, Deborah Stuart, Queren A. Alcantara, Monica P. Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J. Clark, Samir Parikh and Scott A. Summers, 12 November 2025, Cell Metabolism.
DOI: 10.1016/j.cmet.2025.10.006
This research received support from multiple organizations, including an NCRR Shared Instrument Grant, the Kidney Precision Medicine Project, and several branches of the National Institutes of Health. Funding was provided by the National Cancer Institute (P30CA042014, CA272529), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115824, DK116888, DK116450, DK130296, DK108833, DK112826, 1F31DK134088, and 5T32DK091317), and the National Institute of General Medical Sciences (3R35GM131854 and 3R35GM131854-04S1). Additional support came from the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B, awarded to WLH), the Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program (1058616), the American Diabetes Association, the American Heart Association, the Margolis Foundation, and the University of Utah Diabetes and Metabolism Research Center.
Scott Summers and Jeremy Blitzer are co-founders and shareholders of Centaurus Therapeutics. Liping Wang is also a shareholder of Centaurus Therapeutics. DN and Blitzer are named as inventors on U.S. Patents 1177684, 11597715, and 11135207, which are licensed to Centaurus Therapeutics, Inc.
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