Electrochemical biosensors for MLKL-related necroptosis biomarkers in lung cancer: From bench to clinical laboratory

Lung cancer continues to be a leading cause of cancer-related mortality globally, necessitating the development of enhanced biomarkers for early detection and ongoing disease monitoring in clinical practice. Current diagnostic methodologies predominantly rely on imaging and tissue biopsy, which may not sufficiently capture the dynamic molecular alterations occurring during disease progression. Necroptosis is an inflammatory form of regulated cell death that is pathologically relevant in lung cancer. Mixed lineage kinase domain-like protein (MLKL) and its phosphorylated form (pMLKL) have become molecular executors and targets of biomarker clinical applications. In contrast to the available reviews that cover biosensor technologies and regulated cell death in general, this review is uniquely focused on MLKL-centric necroptosis biology and electrochemical biosensing as an analysis gap in clinical laboratory applications. Electrochemical biosensors have emerged as promising analytical platforms for the rapid and sensitive detection of disease-associated targets in complex biological samples. This review critically analyzes recent developments in MLKLs- and pMLKL-related necroptosis biomarkers and electrochemical biosensing approaches for their detection in clinically relevant specimens, such as serum, plasma, and bronchoalveolar lavage fluid (BALF). The focus is on the design of electrode interfaces, biorecognition components such as antibodies, aptamers, and molecularly imprinted polymers, and signal amplification methods. The limitations of traditional techniques such as ELISA, immunohistochemistry, and PCR are critically analyzed when compared to biosensor techniques. An informatics framework bridging laboratory research and clinical applications is proposed, focusing on AI-assisted informatics for the integration of a multimodal MLKL biomarker panel. This study underscores the potential of electrochemical biosensing as a distinctive approach for developing MLKL-specific necroptosis diagnostics in lung cancer.