When the immune system cannot destroy an invader, it does something clever—and sometimes problematic. Macrophages, the body's cleanup crew, clump together around the pathogen or foreign material and wall it off, creating small nodules called granulomas. It's a defensive strategy, sensible in isolation. But for millions of people living with granulomatous skin diseases like granuloma annulare and cutaneous sarcoidosis, these protective nodules become chronic, painful inflammatory patches that no current therapy can truly resolve. An international research team, led by Prof. Dr. Mario Fabri of Jena University Hospital and collaborating with institutions across Europe, has now uncovered the cellular mechanism driving these diseases—and in doing so, revealed unexpected pathways to treatment.
The breakthrough came by studying how macrophages behave when activated by interferon-gamma, a signaling molecule produced by the immune system. Using tissue samples from patients with granuloma annulare and cutaneous sarcoidosis, the researchers traced what happens inside these immune cells. What they discovered was striking: the signaling molecule forces macrophages into what the team describes as "marathon mode"—ramping up oxygen-dependent energy production to sustain prolonged activity, much like an endurance runner shifting into sustained exertion.
At the heart of this process lies a protein called GBP1, which Manuel Huerta, one of the study's first authors, identified as "a key player in this signaling process." The research, published in Science Advances in 2026, maps out a clear biochemical pathway: interferon-gamma activates a cellular respiration chain that depends on GBP1 to sustain the inflammatory response. Understanding this chain immediately suggested where interventions might work.
The implications are immediate and practical. The research supports ongoing clinical trials testing JAK inhibitors—drugs that block interferon-gamma signals—in granulomatous diseases. But the team discovered something equally promising: in cultured tissue from patient samples, they were able to reduce granuloma formation using metformin, the widely used diabetes medication. Rather than blocking the signal entirely, metformin interferes with the respiratory chain itself, essentially preventing macrophages from sustaining their marathon mode of operation.
Henning Klapproth, the study's other first author, emphasizes the broader significance: "Our research opens up new targets for causal therapy in granulomatous diseases. In particular, drug repurposing of metformin is a possible strategy." This is crucial because metformin is already approved, affordable, and familiar to clinicians worldwide—a candidate for rapid translation from laboratory to clinic.
For patients who endure both the physical inflammation and psychological toll of these conditions, the stakes are high. Current treatments manage symptoms but cannot address root causes. Prof. Fabri notes that patients "often suffer significantly—both physically and psychologically—from the extensive skin inflammation, which we can currently treat only symptomatically." With these new mechanistic insights, the path toward genuine causal therapy—targeting the disease process itself rather than merely its appearance—is finally coming into focus. The next phase will be rigorous clinical testing, but the laboratory evidence suggests the immune system's marathon runners may finally meet their match.