For the study, serum samples from 222 NSCLC patients were analyzed. Using advanced LC-MS/MS technologies (liquid chromatography coupled with tandem mass spectrometry), the researchers quantified nine different C-terminal AAT peptides. The study demonstrated that peptides C36, C37, and particularly C42 were most abundant and strongly correlated with overall AAT concentrations in blood. Notably, peptide C42 emerged as an independent prognostic factor for overall survival—even after adjusting for age, sex, tumor stage, and other clinical variables. Moreover, the concentrations of these peptides increased significantly after surgical tumor resection, supporting the assumption that they originate from tumor-associated proteolytic processes. This was further substantiated by additional investigations into matrix metalloproteinase (MMP) expression in tumor tissue, which revealed a close link between elevated MMP activity and increased AAT fragment levels.

Beyond these biomarker insights, Prof. Janciauskiene and her PhD student Sivaraman Kokilavani have uncovered a novel therapeutic angle. In experimental models, they demonstrated that AAT peptides can induce lung cancer cell death via ferroptosis—a form of programmed, iron-dependent cell death triggered by the accumulation of lipid peroxides. Importantly, these AAT-derived peptides markedly enhanced the cytotoxic effects of chemotherapeutic agents such as cisplatin, resulting in synergistically increased cancer cell death. This interaction suggests that AAT peptides may potentiate standard chemotherapy by promoting ferroptotic and oxidative stress-mediated pathways, thereby improving treatment efficacy, particularly in tumors resistant to apoptosis-based therapies. To translate these findings into clinical application, Dr. Janciauskiene together with Hannover Medical School (MHH) submitted a patent application to the European Patent Office in June, 2025.

The findings open several translational perspectives. AAT peptides could in the future help to stratify patients prior to therapy and support the development of individually tailored follow-up strategies. Furthermore, the analysis of these peptides may play an important role in disease monitoring, for example, by detecting changes after tumor resection at an early stage or providing indications of recurrence. In addition, their therapeutic potential as adjunct agents to overcome drug resistance in lung cancer and potentially other solid tumors underscores their relevance far beyond diagnostics. In this way, the study contributes valuable insights to the development of new diagnostic and therapeutic tools that are rooted in the molecular mechanisms of tumor biology and can be directly translated into patient care.

In addition to Prof. Janciauskiene, the research team included Marc Schneider and Dr. Thomas Muley from the DZL site TLRC Heidelberg, as well as partners from Jena and Warsaw. For Janciauskiene, the work underscores the significance of proteomic approaches in translational lung research: “Our data show that AAT fragments provide highly relevant clinical information—even serving as an independent prognostic marker. This opens a new pathway for how proteomic markers can improve the care of patients with lung cancer.”

This publication is an excellent example of how fundamental scientific insights into proteolysis can be translated into clinically applicable concepts. It also highlights the critical importance of close collaboration within the DZL for developing innovative, patient-oriented diagnostics and therapies in thoracic oncology.

Text: BREATH/AB

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