From inhibition to regulation: serpins in health and disease

This issue of the Biomedical Journal highlights regulatory mechanisms that shape aging, disease progression, and biological complexity across molecular, cellular, and systems levels. A central theme is plasminogen activator inhibitor-1 (PAI-1) as a multifunctional regulator linking fibrinolysis, cellular senescence, stem cell dynamics, fibrosis, and tumor biology. Contributions examine structure-guided development of small-molecule PAI-1 inhibitors and their therapeutic potential across thrombotic disease, chronic myeloid leukemia, systemic sclerosis, lung cancer, and skin cancer, emphasizing controlled modulation of PAI-1 activity to preserve physiological balance while overcoming disease-associated dysregulation. Beyond protease signaling, several studies address regulatory layers governing cellular state and adaptability. Epitranscriptomic remodeling via N6-methyladenosine (m6A) emerges as a key mechanism in protozoan parasites and host-pathogen interactions, including parasite-driven reprogramming of host leukocytes. In cancer biology, ferroptosis susceptibility is shown to be regulated through SLC7A11-associated protein interactions, linking redox homeostasis, cell survival, and tumor progression in hepatocellular carcinoma. Exosome-mediated intercellular communication is further examined as a mechanism regulating tissue repair, inflammation, and systemic crosstalk, including gut microbiota-dependent effects on bone homeostasis. Methodological advances further underscore the importance of precision and interpretability in modern biomedical research. These include accessible platforms for reproducible single-cell RNA sequencing analysis, robot-assisted quantification of acupuncture mechanics underlying analgesic responses, and interpretable deep-learning frameworks combining classification and segmentation in medical imaging. Quantitative three-dimensional imaging approaches are also applied to craniofacial surgery, where cone-beam computed tomography-based analyses identify determinants of lip cant and facial midline correction following bimaxillary surgery. A conceptual synthesis places living systems and learning systems within shared theoretical frameworks, highlighting the convergence of physics, information theory, and artificial intelligence in understanding biological organization.