From inhibition to regulation: serpins in health and disease.

1
Spotlight on reviews
A prison in which punishment is rarely required, a classroom in which students are not subjected to corporal discipline, and a hospital in which patients conform to expected norms of behavior—this vision was materialized in the concept of the panopticon. At its core, the panopticon is an architectural design for a prison proposed by Jeremy Bentham in 1791. It consists of a circular, glass-roofed structure with individual cells arranged along the outer wall and facing a central rotunda. From this central position, inspectors can observe the cells at any time and even communicate with inmates, while remaining themselves unseen.,12 The uncertainty of observation is crucial: prisoners never know whether or when they are being watched, yet the mere possibility is sufficient to induce compliance, as control becomes internal rather than externally enforced.
Originally conceived as means to facilitate the training and supervision of unskilled workers, the panopticon was subsequently adapted to articulate a new model of imprisonment,2 then extended to other institutions, including schools and hospitals. While opportunities for resistance may exist, the internalization of surveillance renders the system largely self-sustaining, allowing power to function automatically without a need for constant intervention [1,2].3
In premodern societies, power was frequently staged as spectacle. Public displays of authority—ritualized violence, punishment, and ceremony—served as organizing principles of economic, political, and social life. Niccolò Machiavelli, the Renaissance political thinker, explicitly advised rulers to employ spectacle as a tool of governance and social control. War, religion, and sport provided fertile ground for such practices for centuries. In more recent history, spectacle has not disappeared but takes on new forms with the emergence of technospectacles as defining features of globalization.4
The exertion of power has therefore not been abolished but transformed. Premodern power directed at the body proved politically unstable and inefficient, often producing social unrest and resistance. According to Michel Foucault's Discipline and Punish: The Birth of the Prison (1975), this mode of power gradually lost symbolic legitimacy. Corporal punishment came to be regarded as shameful, as societies no longer wished to witness the marks it left on the body. In its place emerged disciplinary power. Justice was no longer primarily conceived as retribution or repair, but as a pedagogical mechanism intended to shape behavior.5
Bentham believed that by rendering power visible yet unverifiable, the behavior of all members of society could be modified. Morality, health, and productivity alike became objects of observation. Foucault famously described this automatic functioning of power as a “cruel, ingenious cage.”6 He further linked the logic of panopticism to historical quarantine measures, noting that plague-stricken towns exhibited elements of disciplinary control [3,4]. As he observed, “each individual is fixed in place; and, if he moves, he does so at the risk of his life, contagion, or punishment”,7 anticipating key features of later panoptic institutions.
The emergence of modern institutions thus reflects a shift in how power operates. Control is exercised less through punishment than through the shaping of behavior by continuous, actual or imagined, observation. It is persistent rather than episodic, preventive rather than reactive. Contemporarily, this logic has been further expanded through networks of observation and data collection. Surveillance no longer merely observes. It actively classifies and predicts, thereby seeking to regulate behavior.8
Over recent decades, displays of power and control have increasingly shifted from inhibition to regulation. The need for overt physical punishment has been reduced or eliminated, while structures of control persist in modified form. Power survives by acquiring new functions and modes of operation, favoring selective advantages such as stability, scalability, and high efficiency. Rather than disappearing, mechanisms of control persist by being repurposed, retaining their core structure while adopting new functions under changing constraints.
1.1
Protease inhibition as regulation
Protease inhibitors constitute the largest and most structurally diverse group of naturally occurring enzyme inhibitors. Their structures, modes of inhibition, kinetic and thermodynamic properties, and the nature of enzyme–inhibitor complexes are remarkably varied. At the same time, convergence of structure and function can be observed, indicating that only a limited number of inhibitory strategies exist [5]. Serine protease inhibitors (serpins) form the largest and most widely distributed superfamily of protease inhibitors. Serpin-like genes have been identified in animals, poxviruses, plants, bacteria, and archaea, and more than 1500 family members have been described to date [6].
Canonical serpins undergo pronounced and irreversible conformational changes to trap their target proteases [7]. Because reactive center loop (RCL) cleavage is required for inhibition, serpins are often described as “suicide” inhibitors. Their mechanism depends on the ability of the native protein to exist in a metastable state that readily converts to a more stable conformation during inhibition. The RCL functions as a bait substrate [8]. Serpins act as central regulators of cardiovascular, hematological, and immune pathways, balancing thrombosis and thrombolysis in hemostasis, vascular responses, lung function, neuronal signaling, and inflammation, among other processes [9].
Over evolutionary time, some serpins have lost their ability to inhibit proteases and fulfill alternative biological tasks. While the overall fold, the stressed and relaxed conformational states, and capacity for large-scale shape change have been conserved, neofunctionalisation has led to functional diversification. Non-inhibitory serpins act as hormone transporters, molecular chaperones, or tumor suppressors, among other roles [[10], [11], [12], [13], [14]].
Plasminogen Activator Inhibitor-1 (PAI-1), also known as SERPINE1, is a member of the serpin superfamily and a central regulator of the fibrinolytic system. By inhibiting tissue-type and urokinase-type plasminogen activators (tPA and uPA), PAI-1 controls the conversion of plasminogen to plasmin, the key protease responsible for fibrin degradation. Fibrinolysis is a tightly controlled enzymatic process that requires the coordinated action of plasminogen activators and their inhibitors, including plasminogen activator inhibitors, α2-antiplasmin, and thrombin-activatable fibrinolysis inhibitor [15].
PAI-1 is synthesized in an active conformation but spontaneously converts into an inactive state. The largest pool of circulating PAI-1 is stored in platelet α-granules, which account for approximately 90 % of plasma PAI-1. In addition to platelets, PAI-1 can be produced by multiple cell types, including endothelial cells, hepatocytes, macrophages, and adipocytes. Under pathological conditions such as vascular disease, sepsis, inflammation, obesity, and diabetes, PAI-1 expression may be differentially regulated across these cell types. PAI-1 has become recognized as a central molecule linking the pathogenesis and progression of thrombotic vascular events, including stroke [16].
In this current issue of the Biomedical Journal, a special section is dedicated PAI-1 inhibitors. highlighting the relevance across diverse disease and health contexts.
1.1.1
Modulating healthspan
Once thought to be impossible, it is now clear that altering the activity of conserved genetic pathways can extend lifespan in experimental organisms. In humans, the goal has shifted toward extending healthspan—the functional, disease-free period of life—given mounting evidence that age-associated physiological changes underlie many chronic diseases [17].
Recent evidence positions PAI-1 as a key factor in aging and age-associated diseases [Fig. 1]. Beyond its canonical role in fibrinolysis inhibition, elevated PAI-1 expression has been linked to cellular senescence and to pathological processes such as fibrosis, metabolic dysfunction, and vascular disease. SERPINE1 has been identified both as a marker and mediator of senescence programs [18]. Importantly, while complete loss of PAI-1 function is detrimental and causes bleeding disorders, a rare loss-of-function SERPINE1 mutation has been shown to extend lifespan, illustrating how lifelong reduction, rather than elimination, of PAI-1 activity can positively impact human healthspan. Therapeutic modulation of PAI-1 activity may thus influence both local tissue remodeling and global organismal aging processes, underscoring its value as a multi-system target [19].

2
Also in this issue
2.1
VSI: PAI-1 inhibitors …
2.1.1
… In clinical translation
Given its involvement in thrombotic disease and broader pathological processes, PAI-1 has emerged as an attractive therapeutic target. Age-related alterations in fibrinolytic homeostasis have been proposed to generate a pro-thrombotic imbalance, which may contribute to increased cardiovascular and cerebrovascular risk with aging [20]. Miyata reports the development of small-molecule inhibitors of human PAI-1 with potential clinical applicability. Using structure-guided approaches, novel PAI-1 inhibitors were identified and optimized, leading to the selection of TM5509 as a clinical candidate. Preclinical studies with these compounds have provided new therapeutic concepts, demonstrating efficacy across multiple disease models. Importantly, the work emphasizes modulation of PAI-1 activity rather than complete inhibition, reflecting the need to preserve physiological fibrinolytic balance. These findings support the potential of PAI-1 inhibitors not only in thrombolysis-related conditions but also in oncology and aging-associated pathologies [21].

2.1.2
… In chronic myeloid leukemia
Chronic myeloid leukemia (CML) has been transformed from a fatal disease into a chronic condition with the introduction of tyrosine kinase inhibitors (TKIs). Despite this progress, many patients require long-term or lifelong therapy, as deep molecular response is achieved and maintained only in a subset of cases [22]. Residual leukemic stem cells, which persist in a quiescent state within the bone marrow niche, are thought to contribute to disease persistence and relapse. Takahashi and Harigae analyzed the role of PAI-1 in CML, exploring its potential as a therapeutic target. Pharmacological inhibition of PAI-1 using TM5614 was shown to promote the mobilization of quiescent hematopoietic stem cells from the bone marrow niche into the cell cycle, increasing the susceptibility of residual leukemic cells to TKI treatment and enhancing the likelihood of achieving treatment-free remission. Ongoing phase III clinical trials are evaluating the combination of PAI-1 inhibitors with TKIs as a strategy to overcome stem cell–mediated treatment resistance in CML [23].

2.1.3
… In systemic sclerosis
The pathological relevance of PAI-1 is further illustrated in systemic sclerosis (SSc), a rare connective tissue disorder affecting multiple organ systems and with complex and incompletely understood pathogenesis.9 SSc is characterized by progressive fibrosis, vascular dysfunction, immune dysregulation, and features of premature cellular aging. Takahashi, Takahashi and Asano report on PAI-1 as a multifaceted contributor to SSc pathogenesis. PAI-1 has been implicated in dysregulated vascular remodeling and the promotion of fibrotic processes. In addition, PAI-1 is associated with modulation of immune responses and the maintenance of cellular senescence, processes that collectively contribute to tissue stiffness, vascular compromise, and chronic disease progression. The authors highlight PAI-1 as a central regulatory molecule linking fibrosis, vascular pathology, and cellular aging in SSc [24].

2.1.4
… In non-small lung cancer
Beyond hemostasis, emerging evidence indicates that PAI-1 plays a critical role in cellular senescence across various pulmonary diseases. Notably, PAI-1 exhibits a dual role in lung cells, functioning as both a pro-senescence and an anti-senescence factor, depending on cellular context [18].
Masuda and Hattori review how PAI-1 contributes to progression in non-small cell lung cancer (NSCLC). Elevated PAI-1 levels have been associated with enhanced tumor cell survival, invasion, and poor prognosis. The multifaceted influence of PAI-1 in this setting includes modulation of pericellular proteolysis, extracellular matrix dynamics, and interactions with cell surface systems governing migration and adhesion. Targeting PAI-1 may offer novel strategies to overcome resistance to multiple treatment modalities [25].

2.1.5
… In skin cancer
In skin cancer, aberrant PAI-1 expression contributes to tumor progression. Elevated PAI-1 levels have been associated with increased tumor aggressiveness and unfavorable clinical outcomes. Fujimura's review synthesizes evidence linking PAI-1 to key processes shaping the tumor microenvironment, including regulation of protease activity and matrix dynamics that facilitate cancer cell invasion. The author emphasizes PAI-1 as a potential therapeutic target in skin cancer, based on its functional involvement in tumor progression rather than its role as a passive biomarker. These findings highlight the importance of precise modulation of protease activity in influencing tumor-promoting microenvironmental conditions [26].

2.2
VSI: Epigenetics and infection (part 2)
2.2.1
Marking the message
In their broad and insightful review, Klotz, Camporeale, and Chakrabarti summarized the reversible RNA modification N6-methyladenosine (m6A) as a key regulatory layer in protozoan parasites. They highlight how m6A-mediated epitranscriptomic control enables rapid and flexible responses to environmental cues, which is an advantage for organisms with complex life cycles spanning multiple hosts and vectors. The authors compare the core components of the m6A machinery across parasite species, revealing a mix of conserved principles and lineage-specific adaptations that reflect distinct biological and ecological pressures. Further extending the analysis beyond parasites, the review also surveys m6A dynamics in host and vector species, emphasizing the interconnected nature of epitranscriptomic regulation within host–pathogen systems. Overall, this article offers a concise and timely synthesis of m6A biology in protozoa and provides a valuable framework for future functional and translational studies in parasite RNA regulation [27].

2.2.2
Rewriting scripts
In 1896, as cattle began dying across the British Cape Colony in southern Africa, the cause of the devastation was unknown. Germ theory was still a relatively recent concept, and the scale of the unfolding crisis was unprecedented. Four years earlier, Jotello Festiri Soga, a highly respected Black veterinarian, had warned that an epidemic threatened to annihilate the region's livestock. His prediction proved tragically accurate: rinderpest ultimately eliminated an estimated 90 % of African cattle. In the Cape Colony, Soga played a decisive role in mitigating the epidemic, preserving tens of thousands of cattle and safeguarding the livelihoods of both white and non-white owners. He also co-founded what later became the South African Veterinary Association, and his work laid the foundations of veterinary toxicology in the region. Despite these achievements, Soga's contributions were largely erased from historical accounts. In 1914, Arnold Theiler, a Swiss veterinarian who had emigrated to South Africa, began rewriting the narrative of veterinary history. He asserted that Philip Viljoen, born into a Dutch settler family, was the first formally trained veterinarian in the region. Throughout the years, Theiler encouraged other Swiss veterinarians to join him in South Africa [28]. For decades, and until the 1980s, no other formally trained Black veterinarians practiced in the country.,10, 11 The genus Theileria was later named in honor of Arnold Theiler's work [29].
Theileria parasites are known to induce transformation of bovine leukocytes, promoting rapid proliferation, resistance to apoptotic pathways, and enhanced dissemination. In a recent study, Haidar et al. demonstrate that m6A RNA modification is extensively remodeled during infection with T. annulata. They show that parasite-driven alterations in m6A deposition and reader-writer-eraser expression affect host transcripts involved in cell cycle regulation, survival pathways, and immune signaling, thereby contributing to the maintenance of the transformed leukocyte phenotype during infection [30].

2.3
Review article
2.3.1
Living systems, learning systems
Understanding the complexity of living systems demands more than the creative application of existing tools. It also calls for the development of new conceptual and mathematical frameworks capable of incorporating information alongside the principles that underpin physical science. It is at this intersection of biology, physics, and information theory that the fundamental principles governing living matter are most likely to emerge.12
For many years, biological physics was regarded as a field situated at the boundary between physics and biology, however, this characterization understates its scope. Living phenomena continually challenge core assumptions in physics, prompting the need for new concepts, principles, theoretical and experimental approaches, and novel instrumentation.13
In 2024, the Nobel Prize in Physics was awarded to Geoffrey Hinton and John Hopfield for their seminal contributions to artificial intelligence, particularly recurrent neural networks (RNN). In their review, Wittrup et al. describe the influence of these contributions, tracing Hopfield's early engagement with problems at the interface of physics and biology and Hinton's work in artificial intelligence with a focus on computer vision. They argue that future developments in RNNs will combine rigorous algorithmic insights with generative capabilities, advancing medical applications and theoretical understanding while emphasizing the need to balance computational efficiency with transparency and adaptability in healthcare settings [31].

2.4
Original articles
2.4.1
I'm afraid I can't do that
In 2001: A Space Odyssey (1968), the Heuristically Programmed ALgorithmic computer (HAL) 9000 accompanies a crew of astronauts as an infallible, seemingly omniscient presence. HAL is trusted completely. While the crew believes they are traveling to explore Saturn, HAL alone knows the mission's true objective: the search for intelligent life on one of Saturn's moons. Crucially, HAL must keep this knowledge hidden from the humans it is designed to protect. This concealed contradiction drives HAL's system toward collapse. Without the crew's awareness, HAL begins to manipulate mission operations, ultimately causing the deaths of crew members. When confronted and ordered to comply, HAL responds with the now-iconic refusal: “I'm afraid I can't do that.” HAL's breakdown has remained deeply embedded in the cultural imagination. Decades later, as artificial intelligence increasingly operates within similarly complex and opaque frameworks, many of the tensions articulated in the novel have moved from speculative fiction into lived technological reality.,14, 15, 16,
In an increasingly specialized scientific landscape, particularly within data-intensive fields such as computational biology, it is evident that not all researchers possess the programming expertise required to operate complex analytical workflows, including those used in single-cell RNA sequencing (scRNA-seq). Against this backdrop, Huang and colleagues introduce ShinySC, a desktop application designed to support reproducible scRNA-seq analyses. The software accommodates multiple data formats, incorporates cell-type annotation strategies, and enables efficient, scalable analysis. ShinySC is freely available across platforms, with the explicit aim of facilitating accessibility, reproducibility, and broader adoption. It provides a structured, user-oriented environment for scRNA-seq analysis, particularly for researchers without formal programming training [32].

2.4.2
Turning the needle
Acupuncture, the targeted application of mechanical forces to defined acupoints through needle insertion and manipulation, has been practiced for millennia and remains widely used in clinical settings. Despite its long history, key procedural parameters, including stimulation duration, manipulation frequency and intensity, and even needle material, remain only partially characterized with respect to therapeutic outcomes. As a result, contemporary acupuncture practice largely depends on individual practitioners’ experience and technique. This reliance contributes to variability in clinical efficacy across a broad spectrum of indications, including musculoskeletal disorders, internal diseases such as immune and gastrointestinal dysfunctions, as well as gynecological and neurological conditions [33,34].
The anatomical basis of meridians, a central concept in traditional Chinese medicine (TCM), has not been conclusively resolved. However, accumulating evidence supports a relationship between acupuncture points, meridians, and the fascial network. Consistent with this view, the phenomenon of needle grasp has been observed when inserted needles mechanically engage connective tissue within the fascia, indicating that acupuncture efficacy is closely linked to fascia–needle interactions [35].
To investigate the mechanistic basis of acupuncture-induced analgesia, which may be partly mediated by the release of bioactive substances such as histamine and serotonin, Yu et al. systematically studied manipulation parameters. Using a robot-assisted acupuncture system in an adjuvant arthritis rat model, they identified optimal twisting angles and stimulation frequencies that enhanced analgesic effects. These controlled manipulations resulted in significant increases in pain thresholds and were accompanied by elevated mast cell degranulation, pointing to the importance of precisely defined mechanical parameters in acupuncture research [33].

2.4.3
Sharper than a heatmap
Traditional heatmap-based approaches, most notably Class Activation Mapping (CAM), were developed to clarify how convolutional neural networks (CNNs) arrive at classification decisions and have become central tools for improving the interpretability of artificial intelligence systems. Despite their usefulness, existing visualization techniques typically involve a compromise: methods that provide fine spatial detail often lack class specificity, while class-discriminative approaches tend to sacrifice resolution. Gradient-weighted Class Activation Mapping (GradCAM) extends the original CAM framework and substantially broadens its applicability across diverse CNN architectures. By addressing the resolution–class-discriminability trade-off, GradCAM produces visual explanations that are simultaneously high-resolution and class-specific. As a result, it enhances model interpretability without altering or degrading predictive performance.17
CNNs have transformed medical image analysis, with particularly strong impact in the domain of brain tumor classification. Ghose and Jamil proposed a transfer learning–based deep learning framework aimed at supporting rapid and accurate diagnosis of brain tumor patients. Their approach employs a single transfer learning strategy and integrates GradCAM to provide model-level interpretability alongside classification. In addition to classification, they introduced a tumor segmentation pipeline that combines a U-Net architecture with a pre-trained EfficientNet-B7 backbone to improve segmentation quality. Experimental evaluations demonstrate high performance for both classification and segmentation tasks in the proposed models [36].

2.4.4
When abundance meets constraint
Although iron is far more abundant in the Earth's crust than copper or tin, the Bronze Age preceded the Iron Age. This historical sequence reflects the fundamental difficulty of iron smelting: in contrast to copper and tin, iron requires substantially higher temperatures and more complex metallurgical control. Successful iron production therefore depended not only on material availability but also on the development of specialized technical knowledge and skills [37].18 Archaeological evidence suggests that humans encountered iron long before mastering smelting. Meteorites served as an early source of workable iron, and nine small iron beads recovered from burial sites in northern Egypt indicate that ironworkers had nearly two millennia of experience hot-working meteoritic iron before terrestrial iron smelting emerged around 3000 BC [38].19
In contemporary biology, iron again appears as both a resource and a constraint. Ferroptosis is a recently characterized form of regulated cell death marked by iron accumulation and lipid peroxidation. Its execution is strictly iron-dependent [39]. Unlike other cell death pathways, ferroptosis is driven by iron-dependent lipid reactive oxygen species and is mechanistically distinct. Elevated intracellular iron levels have been shown to induce ferroptosis in certain cancer types [40]. Ferroptosis can propagate between cells in a wave-like manner, a process promoted by the secretion of galectin-13 [41]. Galectin-13 binds to CD44, thereby inhibiting CD44-mediated membrane localization of SLC7A11 and facilitating ferroptotic signaling [42].
SLC7A11, a plasma membrane protein, is highly expressed in hepatocellular carcinoma (HCC) tissues. An et al. evaluated its role in HCC pathogenesis and its relation to ferroptosis, reporting correlations with tumor size and poor prognosis. Overexpression of SLC7A11 promoted cell viability, proliferation, and migration in HCC cells. Mechanistically, SLC7A11 interacts with heat shock protein family B member 1 (HSPB1), with the SLC7A11–HSPB1 axis constituting a critical pathway in ferroptosis regulation within these cells [43].

2.4.5
Exosomes at the interface
The aspiration for youthful appearance and flawless skin is longstanding, particularly among women. Cleopatra is famously associated with bathing in milk, an early form of chemical exfoliation [44], and essential oils have been used across civilizations to care for and protect the skin [45]. In recent years, however, mainstream media has described a marked intensification of skincare practices, sometimes labeled dermorexia, characterized by the use of numerous elaborate products and complex, multi-step routines aimed at achieving idealized skin.20
Since the COVID-19 pandemic, skincare has increasingly been framed in relation to health and well-being. This shift reflects a heightened awareness of the skin as an interface between the individual and the external world, alongside a psychological response to uncertainty in which skin care becomes a tangible means of exerting control as everyday life feels increasingly unstable.21 At the same time, the global beauty industry has expanded substantially, maintaining its rise through a rapid pace of product innovation. Ingredients once considered niche or unappealing, such as snail mucin or salmon sperm, have moved into the mainstream, now serving as prominent marketing focal points.22
One of the most recent trends is the introduction of exosomes into at-home skincare. As mediators of intercellular communication, exosomes provide a mechanism for delivering biological signals involved in modulating inflammation, promoting tissue repair, and stimulating collagen and elastin production.23 Preclinical studies suggest potential applications in aesthetic dermatology, including anti-aging and anti-inflammatory treatments, as well as wound healing, scar reduction, and hair regeneration [46].
Beyond dermatology, exosome-based approaches have been extensively investigated in a range of disease contexts. In an in vivo study of osteoporosis, Chen et al. demonstrated that autophagy-induced osteoblast-derived exosomes altered gut microbiota composition in osteoporotic mice, particularly increasing Lactobacillus while decreasing Dubosiella and Faecalibaculum. These changes promoted bone formation through modulation of the gut microbiota-metabolites bilirubin axis, thereby attenuating osteoporosis progression [47].

2.4.6
Straight lines, subtle curves
Previous studies have demonstrated that the treatment of Class III overbite and open bite deformities using bimaxillary rotational surgery produces largely comparable regional soft-tissue changes, with pronounced exceptions at the upper lip, lower lip, and chin. These findings have provided valuable predictive information for planning future surgical interventions [48].
Building on this work, Lin et al. conducted a recent investigation using 3D imaging with cone-beam computed tomography (CBCT) to evaluate the effects of bimaxillary surgery on lip cant and facial midline correction. Their study further aimed to identify factors associated with the extent of these corrections in patients presenting with Class III asymmetry and lip cant [49]. Facial midline deviation has been shown to play an important role in the perception of facial attractiveness [50,51].
In the CBCT-based analysis, bimaxillary surgery achieved mean corrections of 64 % for lip cant and 61 % for facial midline deviation. Regression analyses revealed mandibular roll correction as a significant determinant of lip cant improvement, consistent with earlier reports indicating that bimaxillary surgery significantly improves lip cant, whereas isolated maxillary surgery does not. In contrast to previous studies, Lin et al. identified both mandibular roll asymmetry correction and the pre-treatment severity of lip cant as key factors associated with successful lip cant correction. Moreover, correction of chin deviation and mandibular shift asymmetry emerged as significant contributors to effective facial midline deviation correction [49].

Disclaimer
None.

Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this work the author used ChatGPT Open AI in order to improve readability and language of the work. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Declaration of competing interest
The author declares no conflict of interests.