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A preclinical study at the University of Cologne could open up new treatment options for STING-associated vasculopathy with onset in infancy (SAVI) and benefit a wide spectrum of other currently therapy-resistant genetic diseases / publication in “Nature”
A team of researchers at the University of Cologne’s Center for Biochemistry, together with the Bambino Gesù Pediatric Hospital in Rome, Italy, have discovered a fundamental biological mechanism that directly connects the immune sensor protein STING to inflammatory cell death. The study “STING induces ZBP1-mediated necroptosis independently of TNFR1/FADD”, now published in Nature, shows for the first time that activation of STING is a genetic and biochemical requirement for triggering programmed cell death, a process that, when uncontrolled, drives chronic inflammation.
The research was led by Dr Gianmaria Liccardi, junior group leader at the Institute of Biochemistry I, affiliated with the Center for Molecular Medicine Cologne (CMMC) and the CECAD Cluster of Excellence for Aging Research. His team, including first author of the study Konstantinos Kelepouras, discovered that STING activates another protein, ZBP1, which then drives a type of programmed cell death known as necroptosis. This finding not only clarifies a long-standing question in cell biology of how necroptosis is activated, but also links programmed cell death to the origins of severe inflammatory diseases.
Importantly, the team showed that this mechanism underlies STING-associated vasculopathy with onset in infancy (SAVI), a devastating genetic disorder that affects children and currently has no cure. In collaboration with the Bambino Gesù Pediatric Hospital, the researchers analyzed samples from SAVI patients and found clear evidence that programmed cell death is abnormally activated. In a preclinical mouse model of SAVI, blocking necroptosis machinery alleviated disease symptoms, reduced disease severity, and significantly extended survival.
“Our work demonstrates that STING is not just a regulator of immune signaling, but a direct driver of inflammatory cell death,” says Dr Liccardi. “This means that targeting programmed cell death could open an entirely new therapeutic avenue for SAVI and potentially many other STING-related inflammatory diseases.”
The broader implications go well beyond SAVI. Since the STING pathway is activated in multiple autoinflammatory and autoimmune conditions, therapies that inhibit programmed cell death — and necroptosis in particular — could benefit a wide spectrum of otherwise intractable diseases: The findings pave the way for the development of drugs that block programmed cell death, offering hope not only for children with SAVI but also for patients suffering from a wide range of currently incurable STING-related autoinflammatory syndromes.
The study was led by Dr Gianmaria Liccardi and conducted with contributions from several experts and groups working on cell death and inflammation within the research environment of the University of Cologne, including members of the team of Professor Dr. Henning Walczak at the Center for Biochemistry. The work also benefited from the partnership with the Bambino Gesù Pediatric Hospital in Italy. Dr. Liccardi conceived the study, coordinated its execution, and initiated the collaboration with the clinical partners. “This achievement highlights what young investigators can accomplish when supported by an outstanding research environment and when basic discoveries are directly connected to patient care,” he adds. “I would like to thank my team and especially Konstantinos Kelepouras for the great effort. This breakthrough was made possible by the unique research environment at the University of Cologne, which brings together internationally recognized expertise in cell death and inflammation. The combination of collaborative excellence, high-quality science, and cutting-edge infrastructure provided by the University created the ideal conditions for this discovery.“
This preclinical study must be followed by further studies before drugs can be developed to treat patients with SAVI or other STING-associated diseases.
Dr Gianmaria Liccardi
Center for Biochemistry
+49 221 478 81965
gianmaria.liccardi@uk-koeln.de
https://www.nature.com/articles/s41586-025-09536-4
Dr Gianmaria Liccardi led the study that links the STING protein to the programmed cell death necrop ...
Quelle: Michael Wodak
Copyright: MedizinFotoKöln
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